Azetidine derivatives as CCR-3 receptor antagonists

ABSTRACT

Compounds of formula I 
                         
in free or salt form, wherein Ar, X, Y, R 1 , R 2 , R 3 , R 5 , m, n, p and q have the meanings as indicated in the specification, are useful for treating conditions mediated by CCR3. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.

This invention relates to organic compounds, their preparation and theiruse as pharmaceuticals.

In one aspect the invention provides compounds of formula I

in free or salt form, where

Ar is phenyl optionally substituted by one or more substituents selectedfrom halogen, C₁-C₈-alkyl, cyano or nitro;

R¹ is hydrogen or C₁-C₈-alkyl optionally substituted by hydroxy,C₁-C₈-alkoxy, acyloxy, halogen, carboxy, C₁-C₈-alkoxycarbonyl, —N(R⁴)R⁵,—CON(R⁶)R⁷ or by a monovalent cyclic organic group having 3 to 15 atomsin the ring system;

R² is hydrogen, C₁-C₈-alkyl or C₃-C₁₀-cycloalkyl and R³ is C₁-C₈-alkylsubstituted by phenyl, phenoxy, acyloxy or naphthyl, or R³ isC₃-C₁₀-cycloalkyl optionally having a benzo group fused thereto, aheterocyclic group having 5 to 11 ring atoms of which 1 to 4 are heteroatoms, phenyl or naphthyl, said phenyl, phenoxy or naphthyl groups beingoptionally substituted by one or more substituents selected fromhalogen, cyano, hydroxy, acyl, nitro, —SO₂NH₂, C₁-C₈-alkyl optionallysubstituted by C₁-C₈-alkoxy, C₁-C₈-haloalkyl, C₁-C₈-alkoxy,C₁-C₈-haloalkoxy, C₁-C₈-alkylthio, —SO₂—C₁-C₈-alkyl,C₁-C₈-alkoxycarbonyl, C₁-C₈-acylamino optionally substituted on thenitrogen atom by C₁-C₈-alkyl, C₁-C₈-alkylamino, aminocarbonyl,C₁-C₈-alkylamino-carbonyl, di(C₁-C₈-alkyl)amino,di(C₁-C₈-alkyl)aminocarbonyl, di(C₁-C₈-alkyl)aminocarbonyl-methoxy,

or R² and R³ together with the nitrogen atom to which they are attacheddenote a heterocyclic group having 5 to 10 ring atoms of which 1, 2 or 3are hetero atoms;

R⁴ and R⁵ are each independently hydrogen or C₁-C₈-alkyl, or R⁴ ishydrogen and R⁵ is hydroxy-C₁-C₈-alkyl, acyl, —SO₂R⁸ or —CON(R⁶)R⁷, orR⁴ and R⁵ together with the nitrogen atom to which they are attacheddenote a 5-or 6-membered heterocyclic group;

R⁶ and R⁷ are each independently hydrogen or C₁-C₈-alkyl, or R⁶ and R⁷together with the nitrogen atom to which they are attached denote a 5-or 6-membered heterocyclic group;

R⁸ is C₁-C₈-alkyl, C₁-C₈-haloalkyl, or phenyl optionally substituted byC₁-C₈-alkyl;

X is —C(═O)—, —O—, —CH₂—, or CH(OH);

Y is oxygen or sulfur;

m is 1, 2, 3 or 4; and

n, p and q are each 0 or 1, n+p+q=1 or 2, n+q=1, p+q=1, and when n is 0,p is 0.

Terms used in the specification have the following meanings:

“C₁-C₈-alkyl” as used herein denotes straight chain or branchedC₁-C₈-alkyl, which may be, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight orbranched pentyl, straight or branched hexyl, straight or branchedheptyl, or straight or branched octyl. Preferably, C₁-C₈-alkyl isC₁-C₄-alkyl.

“C₃-C₁₀-cycloalkyl” as used herein may be, for example, cyclopropyl,cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl,methylcyclohexyl, dimethylcyclohexyl, cycloheptyl, bicycloheptyl,cyclooctyl, bicyclooctyl, bicyclononyl, tricyclononyl or tricyclodecyl.

“C₁-C₈-alkoxy” as used herein denotes straight chain or branchedC₁-C₈-alkoxy which may be, for example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight orbranched pentoxy, straight or branched hexyloxy, straight or branchedheptyloxy, or straight or branched octyloxy. Preferably, C₁-C₈-alkoxy isC₁-C₄-alkoxy.

“C₁-C₈-haloalkyl” as used herein denotes C₁-C₈-alkyl as hereinbeforedefined substituted by one or more halogen atoms, preferably one, two orthree halogen atoms.

“C₁-C₈-haloalkoxy” as used herein denotes C₁-C₈-alkoxy as hereinbeforedefined substituted by one or more halogen atoms, preferably one, two orthree halogen atoms.

“Aminocarbonyl” as used herein denotes amino attached through thenitrogen atom to a carbonyl group.

“C₁-C₈-alkylamino” and “di(C₁-C₈-alkyl)amino” as used herein denoteamino substituted respectively by one or two C₁-C₈-alkyl groups ashereinbefore defined, which may be the same or different. PreferablyC₁-C₈-alkylamino and di(C₁-C₈-alkyl)amino are respectivelyC₁-C₄-alkylamino and di(C₁-C₄-alkyl)amino.

“C₁-C₈-alkylaminocarbonyl” and “di(C₁-C₈-alkyl)aminocarbonyl” as usedherein denote aminocarbonyl as hereinbefore defined substitutedrespectively on the nitrogen atom by one or two C₁-C₈-alkyl groups ashereinbefore defined, which may be the same or different. PreferablyC₁-C₈-alkylaminocarbonyl and di(C₁-C₈-alkyl)aminocarbonyl arerespectively C₁-C₄-alkylaminocarbonyl and di(C₁-C₄-alkyl)aminocarbonyl.

“C₁-C₈-alkylthio” as used herein denotes C₁-C₈-alkyl as hereinbeforedefined linked to —S—.

“Acyl” as used herein denotes alkylcarbonyl, for exampleC₁-C₈-alkylcarbonyl where C₁-C₈-alkyl may be one of the C₁-C₈-alkylgroups hereinbefore mentioned, optionally substituted by one or morehalogen atoms; cycloalkylcarbonyl, for example C₃-C₈-cycloalkylcarbonylwhere C₃-C₈-cycloalkyl may be, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5- or 6-memberedheterocyclylcarbonyl having one or two hetero atoms selected fromnitrogen, oxygen and sulfur in the ring, such as furylcarbonyl orpyridylcarbonyl; arylcarbonyl, for example C₆-C₁₀-arylcarbonyl such asbenzoyl; or aralkylcarbonyl, for example C₆ toC₁₀-aryl-C₁-C₄-alkylcarbonyl such as benzylcarbonyl orphenylethylcarbonyl. Preferably acyl is C₁-C₄-alkylcarbonyl.

“Acyloxy” as used herein denotes alkylcarbonyloxy, for exampleC₁-C₈-alkylcarbonyloxy where C₁-C₈-alkyl may be one of the C₁-C₈-alkylgroups hereinbefore mentioned, optionally substituted by one or morehalogen atoms; cycloalkylcarbonyloxy, for exampleC₃-C₈-cycloalkylcarbonyloxy where C₃-C₈-cycloalkyl may be, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl; 5- or 6-membered heterocyclylcarbonyloxy having one or twohetero atoms selected from nitrogen, oxygen and sulfur in the ring, suchas furylcarbonyloxy or pyridylcarbonyloxy; arylcarbonyloxy, for exampleC₆-C₁₀-arylcarbonyloxy such as benzoyloxy; or aralkylcarbonyloxy, forexample C₆ to C₁₀-aryl-C₁-C₄-alkylcarbonyloxy such as benzylcarbonyloxyor phenylethylcarbonyloxy, or aryloxyalkylcarbonyloxy, for example,C₆-C₁₀-aryloxy-C₁-C₈-alkylcarbonyloxy, any of which is optionallysubstituted in the aryl moiety by at least one substituent selected fromC₁-C₈-alkoxy, halogen, C₁-C₈-alkylcarbonyl, aminosulfonyl,C₁-C₈-alkylaminosulfonyl and di(C₁-C₈-alkyl)aminosulfonyl. Preferablyacyloxy is C₁-C₄-alkylcarbonyloxy, or benzoyloxy orphenoxy-C₁-C₄-alkylcarbonyloxy optionally substituted in the benzenering thereof by at least one substituent selected from C₁-C₄-alkoxy,C₁-C₄-alkylcarbonyl or aminosulfonyl.

“Acylamino” as used herein denotes amino substituted by acyl ashereinbefore defined.

“Halogen” as used herein may be fluorine, chlorine, bromine or iodine;preferably it is fluorine, chlorine or bromine.

“C₁-C₈-alkoxycarbonyl” as used herein denotes C₁-C₈-alkoxy ashereinbefore defined attached through the oxygen atom to a carbonylgroup.

“Di-(C₁-C₈-alkyl)aminocarbonylmethoxy” as used herein denotesaminocarbonylmethoxy disubstituted on the amino nitrogen atom byC₁-C₈-alkyl as hereinbefore defined, the two C₁-C₈-alkyl groups beingthe same or different.

“Optionally substituted” means the group referred to can be substitutedat one or more positions by any one or any combination of the radicalslisted thereafter.

In Ar, the phenyl group may be substituted, for example by one, two orthree, preferably one or two halogen atoms, preferably selected fromfluorine and chlorine atoms, or by one or two C₁-C₈-alkyl, cyano ornitro groups, or by C₁-C₈-alkyl and one or two halogen, preferablyfluorine or chlorine, atoms. When there is one halogen substituent, itis preferably para to the indicated group X. When there are two or threehalogen substituents, preferably one is para to the indicated group Xand at least one of the others is ortho to the para-halogen substituent.

R³ as substituted phenyl may, for example, be substituted by one, two,three, four or five, preferably by one, two or three, of theabovementioned substituents. R³ may be, for example, phenyl substitutedby one, two or three substituents selected from halogen, cyano, hydroxy,nitro, C₁-C₄-alkoxy, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxy, —CO—NH₂,di(C₁-C₄-alkyl)aminocarbonylmethoxy, C₁-C₄-alkyl optionally substitutedby C₁-C₄-alkoxy, C₁-C₄-haloalkyl, C₁-C₄-alkylcarbonyl, C₁-C₄-alkylthio,—SO₂—NH₂, —SO₂-C₁-C₄-alkyl, di(C₁-C₄-alkyl)amino,C₁-C₄-alkylaminocarbonyl or C₁-C₄-alkyl-carbonylamino. R³ as substitutedphenyl is preferably phenyl substituted by one or more substituentsselected from cyano, halogen, C₁-C₄-alkyl optionally substituted byC₁-C₄-alkoxy, C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxy, C₁-C₄-alkoxycarbonyl,—CO—NH₂, —SO₂—NH₂, —SO₂—C₁-C₄-alkyl, C₁-C₄-alkyl-aminocarbonyl,di(C₁-C₄-alkyl)aminocarbonyl-methoxy or C₁-C₄-alkyl-carbonylamino,especially cyanophenyl, particularly meta-cyanophenyl, and disubstitutedphenyl where one substituent is C₁-C₄-alkoxy ordi(C₁-C₄-alkyl)aminocarbonylmethoxy, preferably ortho to the bondlinking R³ to the remainder of the molecule shown in formula I, and theother, preferably para to the C₁-C₄-alkoxy group, is C₁-C₄-alkoxy,halogen, cyano or C₁-C₄-alkyl.

When R³ is C₁-C₄-alkyl substituted by optionally substituted phenoxy,the substituent(s) on phenoxy may be, for example, one, two or threesubstituents selected from halogen, cyano, C₁-C₈-alkyl, C₁-C₈-alkoxy orC₁-C₈-alkylcarbonyl.

R³ as a heterocyclic group may be, for example, a group having 5 to 11ring atoms of which one, two, three or four, preferably one or two, arehetero atoms selected from nitrogen, oxygen or sulfur, such as pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl,pyridyl, pyranyl, pyrazinyl, or a 5-, 6- or 7-membered heterocyclic,ring preferably having one or two oxygen or nitrogen ring atoms, fusedto a benzene ring, said heterocyclic group being optionally substitutedby substituents including halogen, C₁-C₄-alkyl optionally substituted byC₁-C₄-alkoxy, C₁-C₄-alkoxy, —SO₂—C₁-C₈-alkyl, C₃-C₁₀-cycloalkyl, phenyl,phenyl-C₁-C₄-alkyl and C₂-C₄-alkynyl.

R² and R³ together with the nitrogen atom to which they are attached asa heterocyclic group may be, for example, a group having a 5- or6-membered ring of which one, two or three are heteroatoms, optionallyfused to a benzene ring, such as piperidyl, piperazinyl, morpholino, orbenzopiperidyl, optionally substituted by one or more substituentsincluding C₁-C₈-alkyl, C₁-C₈-alkoxy, C₃-C₁₀-cycloalkyl and halogen.

R¹ as optionally substituted C₁-C₈-alkyl is preferably optionallysubstituted C₁-C₄-alkyl, especially C₁-C₄-alkyl or substituted methyl orethyl. When R¹ is substituted by a cyclic organic group, the latter maybe a carbocyclic or heterocyclic group, for example a C₃-C₁₅-carbocyclicgroup or a 5- to 7-membered heterocyclic group having one or more,preferably one, two or three, ring hetero atoms selected from nitrogen,oxygen and sulfur. The C₃-C₁₅-carbocyclic group may be, for example, acycloaliphatic group having 3 to 8 carbon atoms, preferably C₅- orC₆-cycloalkyl such as cyclopentyl, methylcyclopentyl or cyclohexyl. TheC₃-C₁₅-carbocyclic group may alternatively be, for example, a C₆-C₁₅aromatic group, such as phenyl, which is unsubstituted or substituted byC₁-C₈-alkyl, C₁-C₈-alkoxy, halogen, cyano, —CON(R⁴)R⁵, —SO₂N(R⁴)R⁵ orC₁-C₈-alkylsulfonylamino where R⁴ and R⁵ are as hereinbefore defined.The heterocyclic group may have one nitrogen, oxygen or sulfur atom inthe ring or it may have two nitrogens, or one oxygen and one or twonitrogens, or one sulfur and one or two nitrogens in the ring. Theheterocyclic group is preferably a heterocyclic aromatic group,especially a 5- or 6-membered heterocyclic group such as furyl,imidazolyl, thiazolyl or pyridyl. Preferred embodiments include those inwhich R¹ is hydrogen or C₁-C₄-alkyl substituted by hydroxy orC₁-C₄-alkoxy.

Throughout this specification and in the claims that follow, unless thecontext requires otherwise, the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

Preferred compounds include those of formula I in free or salt form,where Ar is phenyl substituted by one or two substituents selected fromhalogen and C₁-C₈-alkyl;

R¹ is hydrogen, C₁-C₄-alkyl optionally substituted by hydroxy orC₁-C₈-alkoxy, acyloxy, C₁-C₈-alkyl substituted by benzoyloxy orphenoxy-C₁-C₄-alkylcarbonyloxy which are optionally substituted in thebenzene ring by at least one substituent selected from C₁-C₈-alkoxy,C₁-C₈-alkylcarbonyl and aminosulfonyl, or C₁-C₈-alkyl substituted bynaphthyl;

R² is hydrogen or C₁-C₈-alkyl, and R³ is C₁-C₈-alkyl substituted byphenyl or phenoxy, or C₁-C₈-alkyl substituted by benzoyloxy orphenoxy-C₁-C₈-alkylcarbonyloxy which are optionally substituted in thebenzene ring by at least one substituent selected from C₁-C₈-alkoxy,C₁-C₈-alkylcarbonyl and aminosulfonyl, or C₁-C₈-alkyl substituted bynaphthyl, or R³ is C₃-C₈-cycloalkyl optionally having a benzo groupfused thereto, a heterocyclic group having 5 to 11 ring atoms of whichone or two are hetero atoms, selected from nitrogen, oxygen or sulfur,or phenyl, benzyl or naphthyl, said phenyl, phenoxy and naphthyl groupsbeing optionally substituted by one, two or three substituents selectedfrom halogen, cyano, nitro, hydroxy, C₁-C₈-alkoxy, C₁-C₈-haloalkoxy,C₁-C₈-alkyl, C₁-C₈-alkylcarbonyl, C₁-C₈-alkylthio, di(C₁-C₈-alkyl)aminoor C₁-C₈-alkylcarbonylamino,

or R² and R³, together with the nitrogen atom to which they areattached, denote a heterocyclic group having a N-heterocyclic ringoptionally fused to a benzene ring;

X is —O—, —C(═O)— or —CH₂—;

Y is oxygen or sulfur; and

m is 1, 2, 3 or 4.

Especially preferred compounds include those of formula I in free orsalt form, where Ar is phenyl substituted by one or two substituentsselected from halogen and C₁-C₄-alkyl;

R¹ is hydrogen, C₁-C₄-alkyl optionally substituted by hydroxy orC₁-C₄-alkoxy, acyloxy, C₁-C₄-alkyl substituted by benzoyloxy orphenoxy-C₁-C₄-alkylcarbonyloxy which are optionally substituted in thebenzene ring by at least one substituent selected from C₁-C₄-alkoxy,C₁-C₄-alkylcarbonyl and aminosulfonyl, or C₁-C₄-alkyl substituted bynaphthyl;

R² is hydrogen or C₁-C₄-alkyl, and R³ is C₁-C₄-alkyl substituted byphenyl or phenoxy, or C₁-C₄-alkyl substituted by benzoyloxy orphenoxy-C₁-C₄-alkylcarbonyloxy which are optionally substituted in thebenzene ring by at least one substituent selected from C₁-C₄-alkoxy,C₁-C₄-alkylcarbonyl and aminosulfonyl, or C₁-C₄-alkyl substituted bynaphthyl, or R³ is C₅-C₈-cycloalkyl optionally having a benzo groupfused thereto, a heterocyclic group having 5 to 11 ring atoms of whichone or two are hetero atoms, selected from nitrogen, oxygen or sulfur,or phenyl, benzyl or naphthyl, said phenyl, phenoxy and naphthyl groupsbeing optionally substituted by one, two or three substituents selectedfrom halogen, cyano, nitro, hydroxy, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkyl, C₁-C₄-alkylcarbonyl, C₁-C₄-alkylthio, di(C₁-C₄-alkyl)aminoor C₁-C₄-alkylcarbonylamino,

or R² and R³, together with the nitrogen atom to which they areattached, denote a heterocyclic group having a N-heterocyclic ringoptionally fused to a benzene ring;

X is —O—, —C(═O)— or —CH₂—;

Y is oxygen or sulfur; and

m is 1, 2, 3 or 4.

In a second aspect the present invention provides compounds of formula Iin free or salt form, where

Ar is phenyl optionally substituted by one or more substituents selectedfrom halogen, C₁-C₈-alkyl, cyano or nitro;

R¹ is hydrogen or C₁-C₈-alkyl optionally substituted by hydroxy,C₁-C₈-alkoxy, acyloxy, halogen, carboxy, C₁-C₈-alkoxycarbonyl, —N(R⁴)R⁵,—CON(R⁶)R⁷ or by a monovalent cyclic organic group having 3 to 15 atomsin the ring system;

R² is hydrogen or C₁-C₈-alkyl and R³ is C₁-C₈-alkyl substituted byphenyl, phenoxy, acyloxy or naphthyl, or R³ is C₃-C₁₀-cycloalkyloptionally having a benzo group fused thereto, a heterocyclic grouphaving 5 to 11 ring atoms of which 1 to 4 are hetero atoms, phenyl ornaphthyl, said phenyl, phenoxy or naphthyl groups being optionallysubstituted by one or more substituents selected from halogen, cyano,hydroxy, acyl, nitro, —SO₂NH₂, C₁-C₈-alkyl optionally substituted byC₁-C₈-alkoxy, C₁-C₈-haloalkyl, C₁-C₈-alkoxy, C₁-C₈-haloalkoxy,C₁-C₈-alkylthio, —SO₂-C₁-C₈-alkyl, C₁-C₈-alkoxycarbonyl, C₁-C₈-acylaminooptionally substituted on the nitrogen atom by C₁-C₈-alkyl,C₁-C₈-alkylamino, aminocarbonyl, C₁-C₈-alkylamino-carbonyl,di(C₁-C₈-alkyl)amino, di(C₁-C₈-alkyl)aminocarbonyl,di(C₁-C₈-alkyl)aminocarbonyl-methoxy,

or R² and R³ together with the nitrogen atom to which they are attacheddenote a heterocyclic group having 5 to 10 ring atoms of which 1, 2 or 3are hetero atoms;

R⁴ and R⁵ are each independently hydrogen or C₁₋₈-alkyl, or R⁴ ishydrogen and R⁵ is hydroxy-C₁-C₈-alkyl, acyl, —SO₂R⁸ or —CON(R⁶)R⁷, orR⁴ and R⁵ together with the nitrogen atom to which they are attacheddenote a 5-or 6-membered heterocyclic group;

R⁶ and R⁷ are each independently hydrogen or C₁-C₈-alkyl,

or R⁶ and R⁷ together with the nitrogen atom to which they are attacheddenote a 5- or 6-membered heterocyclic group;

R⁸ is C₁-C₈-alkyl, C₁-C₈-haloalkyl, or phenyl optionally substituted byC₁-C₈-alkyl;

X is —C(═O)—, —O—, —CH₂—, or CH(OH);

Y is oxygen or sulfur;

m is 1, 2, 3 or 4, and

n, p and q are each 0 or 1, n+p+q=1 or 2, n+q=1, p+q=1, and when n is 0,p is 0.

Preferred compounds of formula I in free or salt form include those inwhich Ar is phenyl substituted by one or two substituents selected fromfluorine and chlorine; R¹ is hydrogen, C₁-C₄-alkyl substituted byhydroxy or C₁-C₄-alkoxy, acyloxy, C₁-C₄-alkyl substituted by benzoyloxyor phenoxy-C₁-C₄-alkylcarbonyloxy which are optionally substituted inthe benzene ring by at least one substituent selected from C₁-C₄-alkoxy,C₁-C₄-alkylcarbonyl and aminosulfonyl, or C₁-C₄-alkyl substituted bynaphthyl;

R² is hydrogen or C₁-C₄-alkyl, and R³ is C₁-C₄-alkyl substituted byphenyl or phenoxy, or C₁-C₄-alkyl substituted by benzoyloxy orphenoxy-C₁-C₄-alkylcarbonyloxy which are optionally substituted in thebenzene ring by at least one substituent selected from C₁-C₄-alkoxy,C₁-C₄-alkylcarbonyl and aminosulfonyl, or C₁-C₄-alkyl substituted bynaphthyl, or R³ is C₅-C₈-cycloalkyl optionally having a benzo groupfused thereto, a heterocyclic group having 5 to 11 ring atoms of whichone or two are hetero atoms, selected from nitrogen, oxygen or sulfur,or phenyl, benzyl or naphthyl, said phenyl, phenoxy and naphthyl groupsbeing optionally substituted by one, two or three substituents selectedfrom halogen, cyano, nitro, hydroxy, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkyl, C₁-C₄-alkylcarbonyl, C₁-C₄-alkylthio, di(C₁-C₄-alkyl)aminoor C₁-C₄-alkylcarbonylamino,

or R² and R³, together with the nitrogen atom to which they areattached, denote a heterocyclic group having a N-heterocyclic ringoptionally fused to a benzene ring;

X is —O—, —C(═O)— or —CH₂—;

Y is oxygen; and

m is 2, 3 or 4.

In a third aspect the present invention provides compounds of formula Iin free or salt form, where

Ar is phenyl optionally substituted by one or more substituents selectedfrom halogen, C₁-C₈-alkyl, cyano or nitro;

R¹ is hydrogen or C₁-C₈-alkyl optionally substituted by hydroxy,C₁-C₈-alkoxy, acyloxy, halogen, carboxy, C₁-C₈-alkoxycarbonyl, —N(R⁴)R⁵,—CON(R⁶)R⁷ or by a monovalent cyclic organic group having 3 to 15 atomsin the ring system;

R² is hydrogen or C₁-C₈-alkyl and R³ is C₁-C₈-alkyl substituted byphenyl, phenoxy, acyloxy or naphthyl, or R³ is C₃-C₁₀-cycloalkyloptionally having a benzo group fused thereto, a heterocyclic grouphaving 5 to 11 ring atoms of which 1 to 4 are hetero atoms, phenyl ornaphthyl, said phenyl, phenoxy or naphthyl groups being optionallysubstituted by one or more substituents selected from halogen, cyano,hydroxy, acyl, nitro, C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₁-C₈-alkoxy,C₁-C₈-haloalkoxy, C₁-C₈-alkylthio, C₁-C₈-alkoxycarbonyl, acylamino,C₁-C₈-alkylamino, di(C₁-C₈-alkyl)amino ordi(C₁-C₈-alkyl)aminocarbonylmethoxy, or R² and R³ together with thenitrogen atom to which they are attached denote a heterocyclic grouphaving 5 to 10 ring atoms of which 1, 2 or 3 are hetero atoms;

R⁴ and R⁵ are each independently hydrogen or C₁-C₈-alkyl, or R⁴ ishydrogen and R⁵ is hydroxy-C₁-C₈-alkyl, acyl, —SO₂R⁸ or —CON(R⁶)R⁷, orR⁴ and R⁵ together with the nitrogen atom to which they are attacheddenote a 5-or 6-membered heterocyclic group;

R⁶ and R⁷ are each independently hydrogen or C₁-C₈-alkyl, or R⁶ and R⁷together with the nitrogen atom to which they are attached denote a 5-or 6-membered heterocyclic group;

R⁸ is C₁-C₈-alkyl, C₁-C₈-haloalkyl, or phenyl optionally substituted byC₁-C₈-alkyl;

X is —C(═O)—, —O—, —CH₂—, or CH(OH);

Y is oxygen or sulfur;

m is 1, 2, 3 or 4; and

n, p and q are each 0 or 1, n+p+q=1 or 2, n+q=1, p+q=1, and when n is 0,p is 0.

Preferred compounds of formula I in free or salt form include those inwhich

Ar is phenyl substituted by one or two substituents selected fromfluorine and chlorine;

R¹ is hydrogen, C₁-C₄-alkyl substituted by hydroxy or C₁-C₄-alkoxy,C₁-C₄-alkyl substituted by benzoyloxy or phenoxy-C₁-C₄-alkylcarbonyloxywhich are optionally substituted in the benzene ring by at least onesubstituent selected from C₁-C₄-alkoxy, C₁-C₄-alkylcarbonyl andaminosulfonyl, or C₁-C₄-alkyl substituted by naphthyl;

R² is hydrogen or C₁-C₄-alkyl, and R³ is C₁-C₄-alkyl substituted byphenyl or phenoxy, or C₁-C₄-alkyl substituted by benzoyloxy orphenoxy-C₁-C₄-alkylcarbonyloxy which are optionally substituted in thebenzene ring by at least one substituent selected from C₁-C₄-alkoxy,C₁-C₄-alkylcarbonyl and aminosulfonyl, or C₁-C₄-alkyl substituted bynaphthyl, or R³ is C₅-C₈-cycloalkyl optionally having a benzo groupfused thereto, a heterocyclic group having 5 to 11 ring atoms of whichone or two are hetero atoms, selected from nitrogen, oxygen or sulfur,or phenyl, benzyl or naphthyl, said phenyl, phenoxy and naphthyl groupsbeing optionally substituted by one, two or three substituents selectedfrom halogen, cyano, nitro, hydroxy, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkyl, C₁-C₄-alkylcarbonyl, C₁-C₄-alkylthio, di(C₁-C₄-alkyl)aminoor C₁-C₄-alkylcarbonylamino,

or R² and R³, together with the nitrogen atom to which they areattached, denote a heterocyclic group having a N-heterocyclic ringoptionally fused to a benzene ring;

X is —O—, —C(═O)— or —CH₂—;

Y is oxygen; and

m is 2, 3 or 4.

Especially preferred compounds of formula I in free or salt forminclude:

(1) Compounds of Formula II

where

Ar is phenyl substituted by one or two substituents selected fromfluorine and chlorine, one of said substituents being para to theindicated group X;

R¹ is hydrogen, C₁-C₄-alkyl substituted by hydroxy or C₁-C₄-alkoxy,C₁-C₄-alkyl substituted by benzoyloxy or phenoxy-C₁-C₄-alkylcarbonyloxywhich are optionally substituted in the benzene ring by at least onesubstituent selected from C₁-C₄-alkoxy, C₁-C₄-alkylcarbonyl andaminosulfonyl, or C₁-C₄-alkyl substituted by naphthyl;

R³ is phenyl substituted by one, two or three substituents selected fromhalogen, cyano, di(C₁-C₄-alkyl)amino, C₁-C₄-alkylcarbonylamino orC₁-C₄-alkoxy, or R³ is naphthyl optionally substituted by fluorine, orR³ is C₁-C₄-alkyl substituted by phenoxy which is optionally substitutedby one or two substituents selected from halogen, cyano, C₁-C₄-alkyl,C₁-C₄-alkoxy or C₁-C₄-alkylcarbonyl, or R³ is C₁-C₄-alkyl substituted bybenzoyloxy or phenoxy-C₁-C₄-alkylcarbonyloxy which are optionallysubstituted in the benzene ring by at least one substituent selectedfrom C₁-C₄-alkoxy, C₁-C₄-alkylcarbonyl and aminosulfonyl, or R³ is aheterocyclic group having a 5- or 6-membered heterocyclic ring in whichone or two ring atoms are hetero atoms selected from nitrogen, oxygenand sulfur optionally fused to a benzene ring which is optionallysubstituted by one or two substituents selected from halogen,C₁-C₄-alkoxy and C₁-C₄-alkylcarbonyl;

X is —O—; and

m is 2 or 3.

(2) Compounds of Formula III

where

Ar is phenyl substituted by one or two substituents selected fromfluorine and chlorine, one of said substituents being para to theindicated group X;

R¹ is hydrogen, C₁-C₄-alkyl substituted by hydroxy or C₁-C₄-alkoxy;

R² is hydrogen or C₁-C₄-alkyl and R³ is C₅-C₉-cycloalkyl, a heterocyclicgroup having 5 to 11 ring atoms of which one or two are nitrogen oroxygen atoms, phenyl optionally substituted by one, two or threesubstituents selected from fluorine, chlorine, hydroxy, nitro,C₁-C₄-alkyl, C₁-C₄-alkylcarbonyl or C₁-C₄-alkoxy, phenyl-C₁-C₄-alkylsubstituted in the phenyl group by one or two substituents selected fromhalogen and C₁-C₄-alkyl, C₁-C₄-alkyl substituted by naphthyl, orC₅-C₆-cycloalkyl having a benzo group fused thereto, or R² and R³together with the nitrogen atom to which they are attached denote aheterocyclic group having a 6-membered N-heterocyclic ring fused to abenzene ring which is optionally substituted by up to 2 C₁-C₄-alkoxygroups;

X is —O— or —C(═O)—; and

m is 2 or 3.

(3) Compounds of Formula III Where

Ar is phenyl substituted by chlorine para to the indicated group X andoptionally also substituted by chlorine meta to the indicated group X;

R¹ is hydrogen or C₁-C₄-alkyl substituted by hydroxy, C₁-C₄-alkoxy orC₁-C₄-acyloxy;

R² is hydrogen;

R³ is a heterocyclic group having 5 to 11 ring atoms of which 1 to 4 arehetero atoms selected from nitrogen, oxygen and sulphur or atoms,preferably a heterocyclic ring having 5 atoms of which 1 to 4 areheteroatoms selected from nitrogen, oxygen and sulphur substituted byone or two substituents selected from C₁-C₄-alkyl, C₃-C₆-cycloalkyl and—SO₂—C₁-C₄-alkyl, or R³ is phenyl optionally substituted by one, two orthree substituents selected from halogen, cyano, C₁-C₄-alkyl optionallysubstituted by C₁-C₄-alkoxy, C₃-C₆-cycloalkyl, C₁-C₄-alkoxy,C₁-C₄-alkoxycarbonyl, (C₁-C₄-alkyl)aminocarbonyl,di(C₁-C₄-alkyl)aminocarbonyl, aminocarbonyl, —SO₂NH₂, —SO₂—C₁-C₄-alkyland C₁-C₄-acylamino optionally substituted on the nitrogen atom byC₁-C₄-alkyl;

X is —O—, —CH₂— or —C(═O)—; and

m is 2.

(4) Compounds of Formula IIIa

where

Ar is phenyl optionally substituted by fluoro or chloro para to theindicated group X and/or optionally substituted by fluoro, chloro orC₁-C₄-alkyl meta to the indicated group X;

R¹ is hydrogen or C₁-C₄-alkyl optionally substituted by hydroxy;

R² is hydrogen or C₁-C₄-alkyl;

R³ is C₃-C₆-cycloalkyl, or R³ is a heterocyclic group having 5 to 11ring atoms of which 1 to 4 are hetero atoms selected from nitrogen,oxygen and sulphur or atoms, preferably a heterocyclic ring having 5atoms of which 1 to 4 are heteroatoms selected from nitrogen, oxygen andsulphur substituted by one or two substituents selected from C₁-C₄-alkyland C₃-C₆-cycloalkyl, or R³ is phenyl substituted by C₁-C₄-alkoxy;

X is —O—, —CH₂— or —C(═O)—;

Y is O or S; and

m is 1 or 2.

(5) Compounds of Formula IV

where

Ar is phenyl substituted by one or two substituents selected fromfluorine and chlorine, one of said substituents being para to theindicated group X;

R¹ is hydrogen or C₁-C₄-alkyl substituted by hydroxy or C₁-C₄-alkoxy;

R³ is phenyl optionally substituted by halogen, C₁-C₄-alkyl or cyano, orR³ is an aromatic N- or S-heterocyclic group having 5 to 10 ring atoms,or R³ is phenyl-C₁-C₄-alkyl;

X is —O—; and

m is 2 or 3.

The compounds represented by formula I are capable of forming acidaddition salts, particularly pharmaceutically acceptable acid additionsalts. Pharmaceutically acceptable acid addition salts of the compoundof formula I include those of inorganic acids, for example, hydrohalicacids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid orhydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; andorganic acids, for example aliphatic monocarboxylic acids such as formicacid, acetic acid, trifluoroacetic acid, propionic acid and butyricacid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaricacid or malic acid, dicarboxylic acids such as maleic acid or succinicacid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoicacid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxyacids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid,1-hydroxynaphthalene-2-carboxylic acid or3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such asmethanesulfonic acid or benzenesulfonic acid. These salts may beprepared from compounds of formula I by known salt-forming procedures.

Compounds of formula I which contain acidic, e.g. carboxyl, groups, arealso capable of forming salts with bases, in particular pharmaceuticallyacceptable bases such as those well known in the art; suitable suchsalts include metal salts, particularly alkali metal or alkaline earthmetal salts such as sodium, potassium, magnesium or calcium salts, orsalts with ammonia or pharmaceutically acceptable organic amines orheterocyclic bases such as ethanolamines, benzylamines or pyridine.These salts may be prepared from compounds of formula I by knownsalt-forming procedures.

When R¹ is other than hydrogen, the carbon atom to which R¹ is attachedin formula I is asymmetric, in which case the compounds exist inindividual optically active isomeric forms or as mixtures thereof, e.g.as racemic or diastereomeric mixtures. The invention embraces bothindividual optically active R and S isomers as well as mixtures, e.g.racemic or diastereomeric mixtures, thereof.

Specific especially preferred compounds of the invention are thosedescribed hereinafter in the Examples.

The invention also provides a process for the preparation of compoundsof formula I which comprises

-   (i) (A) for the preparation of compounds of formula I where n is 1,    p is 1, q is 0 and R² is hydrogen, reacting a compound of formula V

-   -   where Ar, X, m and R¹ are as hereinbefore defined, with a        compound of formula VI        Y═C═N—R³  VI    -   where Y and R³ are as hereinbefore defined, with the proviso        that when R¹ contains a reactive functional group it may be in        protected form, and, where R¹ in the product contains a        protected functional group, replacing the protecting group by        hydrogen;    -   (B) for the preparation of compounds of formula I where n is 1,        p is 1, q is 0 and R² is hydrogen or C₁-C₈-alkyl, reacting a        compound of formula VII

-   -   where Ar, X, m and R¹ are as hereinbefore defined, with a        compound of formula VIII

-   -   where R² and R³ are as hereinbefore defined, or and, where R¹ in        the product contains a protected functional group, replacing the        protecting group by hydrogen;    -   (C) for the preparation of compounds of formula I where n is 1,        p is 1, q is 0 and R² and R³ together with the nitrogen atom to        which they are attached denote a heterocyclic group, reacting a        compound of formula IX

-   -   where Ar and X are as hereinbefore defined, with a compound of        formula X

-   -   where m, R¹ and Y are as hereinbefore defined, R² and R³        together with the nitrogen atom to which they are attached        denote a heterocyclic group having 5 to 10 ring atoms of which        one, two or three are hetero atoms, and L is halogen, preferably        bromine;    -   (D) for the preparation of compounds of formula I when n is 1, p        is 0, q is 0 and Y is oxygen, reacting a compound of formula IX        where Ar and X are as hereinbefore defined, with a compound of        formula XI

-   -   where L, m, R¹ and R³ are as hereinbefore defined;    -   (E) for the preparation of compounds of formula I where n is 1,        p is 0, q is 0 and Y is oxygen, reacting a compound of formula V        where Ar, X, m and R¹ are as hereinbefore defined, with a        compound of formula XII

-   -   where R³ is as hereinbefore defined, and, where R¹ in the        product contains a protected functional group, replacing the        protecting group by hydrogen;    -   (F) for the preparation of compounds of formula I where n is 1,        p is 0, q is 0, R² is hydrogen and Y is oxygen, reacting a        compound of formula V where Ar, X, m and R¹ are as hereinbefore        defined, with a compound of formula XIII

-   -   where R³ is as hereinbefore defined, and, where R¹ in the        product contains a protected functional group, replacing the        protecting group by hydrogen;    -   (G) for the preparation of compounds of formula I where n is 0,        p is 0, and q is 1, reacting a compound of formula IX where Ar        and X are as hereinbefore defined in the form of a hydrohalide        salt with a compound of formula XIV

-   -   where L, m, R¹ and R³ are as hereinbefore defined;    -   (H) for the preparation of compounds of formula I where n is 1,        p is 1, q is 0 and Y is oxygen, reacting a compound of formula V        where Ar, X, m and R¹ are as hereinbefore defined, with a        compound of formula XV

-   -   where R² and R³ are as hereinbefore defined; or    -   (I) for the preparation of compounds of formula I where n is 1,        p is 0, q is 0, Y is oxygen and R² is C₁-C₈-alkyl or        C₃-C₁₀-cycloalkyl, reacting a compound of formula V where Ar, X,        m and R¹ are as hereinbefore defined, with a compound of formula        XVI

-   -   where R² is C₁-C₈-alkyl or C₃-C₁₀-cycloalkyl, R³ is as        hereinbefore defined and Z is a halogen, with the proviso that        when R¹ contains a reactive functional group it may be in        protected form, and, where R¹ in the product contains a        protected functional group, replacing the protecting group by        hydrogen; and

-   (ii) recovering the product in free or salt form.

Process variant (A) may be effected using known procedures for reactionof amines with isocyanates or analogously e.g. as hereinafter describedin the Examples. The reaction is conveniently carried out in an organicsolvent, for example a halohydrocarbon such as dichloromethane (DCM) oran ether such as dioxane. The reaction temperature may be e.g. from 0°C. to 100° C., conveniently ambient temperature.

Process variant (B) may be effected using known procedures for reactionof carbamic acid phenyl esters with amines or analogously e.g. ashereinafter described in the Examples. The reaction is convenientlycarried out in an organic solvent such as dimethyl sulfoxide (DMSO). Thereaction temperature may be e.g. from 0 to 100° C., conveniently ambienttemperature.

Process variant (C) may be effected using known procedures for reactionof heterocyclic secondary amines with haloalkylureas or analogously e.g.as hereinafter described in the Examples. The reaction is usuallyeffected between the hydrochloride salt of the compound of formula IXand the compound of formula X in the presence of a tertiary amine. Thereaction is conveniently effected in an organic solvent, e.g. ahalohydrocarbon such as DCM. The reaction temperature may be e.g. from 0to 100° C., conveniently ambient temperature.

Process variant (D) may be effected using known procedures for reactionof heterocyclic secondary amines with N-(haloalkyl) amides oranalogously e.g. as hereinafter described in the Examples. It is usuallyeffected between the hydrochloride salt of the compound of formula IXand the compound of formula XI in the presence of a tertiary amine.Reaction is conveniently effected in an organic solvent such asacetonitrile. The reaction temperature may be e.g. from 0 to 100° C.,conveniently ambient temperature.

Process variant (E) may be effected using known procedures foramide-forming reaction of amines with acid halides or analogously.

Process variant (F) may be effected using known procedures for amideformation, for example by reaction in the presence of a tertiary amineand a peptide coupling agent, conveniently in an organic solvent, e.g. ahalohydrocarbon such as DCM. The reaction temperature may be e.g. from 0to 40° C., conveniently ambient temperature.

Process variant (G) may be effected using known procedures for reactionof heterocyclic secondary amines with N-(haloalkyl) sulfonamides oranalogously e.g. as hereinafter described in the Examples. It is usuallyeffected in the presence of a tertiary amine, conveniently in an organicsolvent such as acetonitrile. The reaction temperature may be e.g. from0 to 100° C., conveniently ambient temperature.

Process variant (H) may be effected using known procedures for reactionof amines with carbamic acid phenyl esters or analogously e.g. ashereinafter described in the Examples. The reaction is convenientlycarried out in an organic solvent such as dimethyl sulfoxide (DMSO). Thereaction temperature may be e.g. from 20 to 100° C., convenientlyambient temperature.

Process variant (I) may be effected using known procedures foramide-forming reaction of amines with halo-formamides or analogouslye.g. as hereinafter described in the Examples. The reaction temperaturemay be e.g. from 0 to 40° C., conveniently ambient temperature.

Compounds of formula V may be prepared by reacting a compound of formulaIX with a compound of formula XVII

where R¹, L and m are as hereinbefore defined, with the proviso thatwhen R¹ contains a reactive functional group such as a hydroxy group,the reactive group may be in protected form, for example a hydroxy groupprotected as a tert-butoxy group, and R⁹ is hydrogen or anamine-protective group, for example a tert-butoxycarbonyl group, and,where R⁹ is a protective group, replacing R⁹ in the product by hydrogen,and, where R¹ in the product contains a protected functional group,replacing the protecting group by hydrogen. When R⁹ is hydrogen,reaction between a compound of formula XVII and a salt of a compound offormula IX may be effected by the procedures described in U.S. Pat. No.4,559,349. When R⁹ is a protective group, reaction between compounds offormulae XVII and IX may be effected using known methods, for example inthe presence of a tertiary organic base such as triethylamine or1,8-diaza-bicyclo [5.4.0]undec-7-ene (DBU), conveniently in an inertorganic solvent, for example a polar solvent such as dimethylformamide,the reaction temperature suitably being from 0 to 40° C., preferablyambient temperature. Replacement of a protective group R⁹ by hydrogenmay be effected using known procedures; for example, where R⁹ istert-butoxycarbonyl, by treatment with a carboxylic acid such astrifluoroacetic acid. Replacement of a protecting group in R¹ may beaffected using known procedures, for example, when R¹ contains a hydroxygroup protected as an ether group, such as tert-butoxy, by treatmentwith HBr in a carboxylic acid such as acetic acid; when R⁹ is aprotective group, this treatment also replaces R⁹ by hydrogen.

Where reference is made herein to protected functional groups or toprotecting groups, the protecting groups may be chosen in accordancewith the nature of the functional group, for example as described inProtective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,John Wiley & Sons Inc, Second Edition, 1991, which reference alsodescribes procedures suitable for replacement of the protecting groupsby hydrogen.

Compounds of formulae VI are commercially available or may be preparedby known methods.

Compounds of formula VII may be prepared by reacting a compound offormula V with phenyl chloroformate in the presence of a base such as atertiary amine, for example as hereinafter described in the Examples.

Compounds of formulae VIII are commercially available or may be preparedby known methods.

Compounds of formula IX where X is —O— may be prepared by reacting acompound of formula XVIII

with a compound of formula Ar—OH in the presence of sodium hydride,where Ar is as hereinbefore defined and R¹⁰ is a protecting group, andreplacing R¹⁰ in the product by hydrogen. The reaction may be carriedout in an inert organic solvent such as DMF. Suitable reactiontemperatures may be from 20° C. to 150° C., conveniently from 50 to 70°C. The replacement of R¹⁰ by hydrogen may be affected using knownprocedures, for example where R¹⁰ is benzhydryl by reacting the productof the reaction of the compound of formula XVII and Ar¹—OH with1-chloroethyl chloroformate, a suitable reaction temperature being10-30° C., conveniently at room temperature.

Compounds of formula IX where X is —C(═O)— may be prepared by reacting acompound of formula XIXa or formula XIXb

with a compound of formula XXAr═MgBr  XXwhere Ar and R¹⁰ are as hereinbefore defined, and replacing R¹⁰ in theproduct by hydrogen. Reaction of compounds of formulae XIXa/b and XX maybe effected in an inert organic solvent, e.g. an ether such as THFand/or diethyl ether; suitable reaction temperatures may be from −10° C.to 10° C., conveniently from −5 to 5° C. Replacement of R¹⁰ in theproduct by hydrogen may be effected as hereinbefore described.

Compounds of formula IX where X is —CH₂— are novel and may be preparedby reduction of compounds of formula IX where X is —C(═O)—, for exampleusing known reduction procedures. This preferably involves of reductionto the corresponding alcohol, conversion to the iodine and thenreduction.

Compounds of formula X may be prepared by reaction of a compound offormula XXI

with a compound of formula H—N(R²)R³ where L, R¹, R² and R³ are asdefined in formula X, for example as hereinafter described in theExamples.

Compounds of formula XI may be prepared by reaction of a compound offormula XXII

with a compound of formula XIII, for example as hereinafter described inthe Examples.

Compounds of formulae XII and XIII are known or may be prepared by knownprocedures.

Compounds of formula XIV may be prepared by reacting a compound offormula XXII with a compound of formula R³SO₂Cl, for example ashereinafter described in the Examples.

Compounds of formulae XV, XVI, XVII, XVIII are known or may be preparedby known procedures.

Compounds of formula XIXa may be prepared by reacting a compound offormula XXIII

with O,N-dimethylhydroxylamine hydrochloride in the presence of apeptide coupling agent such as di-imidazol-1-yl-methanone, convenientlyin an inert organic solvent such as THF, suitably at reflux temperature.

Compounds of formulae XIXb, XX, XX, XXII and XXII are known or may beprepared using known procedures.

Compounds of formula I in free form may be converted into salt form, andvice versa, in a conventional manner. The compounds in free or salt formcan be obtained in the form of hydrates or solvates containing a solventused for crystallization. Compounds of formula I can be recovered fromreaction mixtures and purified in a conventional manner. Isomers, suchas enantiomers, may be obtained in a conventional manner, e.g. byfractional crystallization or asymmetric synthesis from correspondinglyasymmetrically substituted, e.g. optically active, starting materials.

Compounds of formula I in free or pharmaceutically acceptable salt form,hereinafter referred to alternatively as agents of the invention, areuseful as pharmaceuticals. Accordingly the invention also provides acompound of formula I in free or pharmaceutically acceptable salt formfor use as a pharmaceutical. The agents of the invention act as CCR-3receptor antagonists, thereby inhibiting the infiltration and activationof inflammatory cells, particularly eosinophils, and inhibiting allergicresponse. The inhibitory properties of agents of the invention can bedemonstrated in the following assay:

CCR-3 Binding Assay

In this assay the effect of agents of the invention on the binding ofhuman eotaxin to human CCR-3 is determined. Recombinant cells expressinghuman CCR-3 are captured by wheatgerm agglutinin (WGA)polyvinyltoluidene (PVT) SPA beads (available from Amersham), through aspecific interaction between the WGA and carbohydrate residues ofglycoproteins on the surface of the cells. [¹²⁵I]-human eotaxin(available from Amersham) binds specifically to CCR-3 receptors bringingthe [¹²⁵I]-human eotaxin in close proximity to the SPA beads. Emittedâ-particles from the [¹²⁵I]-human eotaxin excite, by its proximity, thefluorophore in the beads and produce light. Free [¹²⁵I]-human eotaxin insolution is not in close proximity to the scintillant and hence does notproduce light. The scintillation count is therefore a measure of theextent to which the test compound inhibits binding of the eotaxin to theCCR-3.

Preparation of Assay Buffer: 5.96 g HEPES and 7.0 g sodium chloride aredissolved in distilled water and 1M aqueous CaCl₂ (1 ml) and 1M aqueousMgCl₂ (5 ml) are added. The pH is adjusted to 7.6 with NaOH and thesolution made to a final volume of 1 L using distilled water. 5 g bovineserum albumin and 0.1 g sodium azide are then dissolved in the solutionand the resulting buffer stored at 4° C. A Complete™ protease inhibitorcocktail tablet (available from Boehringer) is added per 50 ml of thebuffer on the day of use.

Preparation of Homogenisation Buffer: Tris-base (2.42 g) is dissolved indistilled water, the pH of the solution is adjusted to 7.6 withhydrochloric acid and the solution is diluted with distilled water to afinal volume of 1 l. The resulting buffer is stored at 4° C. A Complete™protease inhibitor cocktail tablet is added per 50 ml of the buffer onthe day of use.

Preparation of membranes: Confluent rat basophil leukemia (RBL-2H3)cells stably expressing CCR3 are removed from tissue culture flasksusing enzyme-free cell dissociation buffer and resuspended inphosphate-buffered saline. The cells are centrifuged (800 g, 5 minutes),the pellet resuspended in ice-cold homogenisation buffer using 1 mlhomogenisation buffer per gram of cells and incubated on ice for 30minutes. The cells are homogenised on ice with 10 strokes in a glassmortar and pestle. The homogenate is centrifuged (800 g, 5 minutes, 4°C.), the supernatant further centrifuged (48,000 g, 30 minutes, 4° C.)and the pellet redissolved in Homogenisation Buffer containing 10% (v/v)glycerol. The protein content of the membrane preparation is estimatedby the method of Bradford (Anal. Biochem. (1976) 72:248) and aliquotsare snap frozen and stored at −80° C.

The assay is performed in a final volume of 250 μl per well of anOptiplate™ microplate (ex Canberra Packard). To selected wells of theOptiplate™ are added 50 μl of solutions of a test compound in AssayBuffer containing 5% DMSO (concentrations from 0.01 nM to 10 μM). Todetermine total binding, 50 μl of the Assay Buffer containing 5% DMSO isadded to other selected wells. To determine non-specific binding, 50 μlof 100 nM human eotaxin (ex R&D Systems) in Assay Buffer containing 5%DMSO is added to further selected wells. To all wells are added 50 μl[¹²⁵I]-Human eotaxin (ex Amersham) in Assay Buffer containing 5% DMSO ata concentration of 250 μM (to give a final concentration of 50 μM perwell), 50 μl of WGA-PVT SPA beads in Assay Buffer (to give a finalconcentration of 1.0 mg beads per well) and 100 μl of the membranepreparation at a concentration of 100 μg protein in Assay Buffer (togive a final concentration of 10 μg protein per well). The plate is thenincubated for 4 hours at room temperature. The plate is sealed usingTopSeal-S™ sealing tape (ex Canberra Packard) according to themanufacturers instructions. The resulting scintillations are countedusing a Canberra Packard TopCount™ scintillation counter, each wellbeing counted for 1 minute. The concentration of test compound at which50% inhibition occurs (IC₅₀) is determined from concentration-inhibitioncurves in a conventional manner.

The compounds of the Examples hereinbelow generally have IC₅₀ valuesbelow 1 μM in the above assay. For instance, the compounds of Examples16, 26, 37, 45, 83, 88, 99, 122, 134, 190 and 195 have IC₅₀ values of0.103 μM, 0.007 μM, 0.018 μM, 0.011 μM, 0.005 μM, 0.006 μM, 0.007 μM,0.022 μM, 0.012 μM, 0.011 μM, and 0.002 μM respectively.

Most of the compounds of the Examples exhibit selectivity for inhibitionof CCR-3 binding relative to inhibition of binding of the alpha-1adrenergic receptor. Some of the compounds, e.g. that of Example 190,are also histamine H1 antagonists. The inhibitory properties of agentsof the invention on binding of the alpha-1 adrenergic receptor can bedetermined in the following assay:

Cerebral cortices from male Sprague-Dawley rats (175-200 g) aredissected and homogenised in 10 volumes of ice cold 0.32 M sucrose(containing 1 mM MgCl₂ dihydrate and 1 mM K₂HPO₄) with a glass/teflonhomogeniser. The membranes are centrifuged at 1000×g for 15 miN, thepellet discarded and the centrifugation repeated. The supernatants arepooled and centrifuged at 18,000×g for 15 minutes. The pellet isosmotically shocked in 10 volumes of water and kept on ice for 30minutes. The suspension is centrifuged at 39,000×g for 20 minutes,resuspended in Krebs-Henseleit buffer pH 7.4 (1.17 mM MgSO₄ anhydrous,4.69 mM KCl, 0.7 mM K₂HPO₄ anhydrous, 0.11 M NaCl, 11 mM D-glucose and25 mM NaHCO₃) containing 20 mM Tris, and kept for 2 days at −20° C. Themembranes are then thawed at 20-23° C., washed three times withKrebs-Henseleit buffer by centrifugation at 18,000×g for 15 minutes,left overnight at 4° C. and washed again three times. The final pelletis resuspended with a glass/teflon homogeniser in 125 ml/100 membranesin the same buffer. A sample is taken to determine the proteinconcentration (using the Bradford Assay with gamma globulin as thestandard) and the remainder aliquoted and stored at −80° C.

The resulting membranes are subjected to a radioligand binding assay.The assay is conducted in triplicate using 96 well plates containing[¹²⁵I]-HEAT (Amersham) (40 pM, K_(d): 58.9±18.7 pM), unlabelled testcompound and membrane (57.1 μg/ml) to yield a final volume of 250 μl(assay buffer containing 50 mM Tris-base and 0.9% (w/v) NaCl, pH 7.4).The plates are incubated at 37° C. for 60 minutes, after which rapidvacuum filtration over Whatman™ GF/C 96 well filter plates is carriedout. Each plate is then washed three times with 10 ml of ice cold assaybuffer using a Brandel Cell harvester (Gaithersburg, Md.). Followingdrying of the plates for 3 h. at 50° C., 40 μl of Microscint 20 is addedto each well, the plates incubated at room temperature for a further 20minutes and the retained radioactivity quantified in a Packard TopCountNXT™ scintillation counter.

Stock solutions of test compounds are dissolved initially in 100% DMSOand diluted with assay buffer to the required concentrations to yield 1%(v/v) DMSO.

The concentration of test compound at which 50% inhibition occurs (IC₅₀)is determined from concentration-inhibition curves in a conventionalmanner.

Having regard to their inhibition of binding of CCR-3, agents of theinvention are useful in the treatment of conditions mediated by CCR-3,particularly inflammatory or allergic conditions. Treatment inaccordance with the invention may be symptomatic or prophylactic.Accordingly, agents of the invention are useful in the treatment ofinflammatory or obstructive airways diseases, resulting, for example, inreduction of tissue damage, bronchial hyperreactivity, remodelling ordisease progression. Inflammatory or obstructive airways diseases towhich the present invention is applicable include asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial or viral infection. Treatment ofasthma is also to be understood as embracing treatment of subjects, e.g.of less than 4 or 5 years of age, exhibiting wheezing symptoms anddiagnosed or diagnosable as “wheezy infants”, an established patientcategory of major medical concern and now often identified as incipientor early-phase asthmatics. (For convenience this particular asthmaticcondition is referred to as “wheezy-infant syndrome”.)

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, i.e. therapy for or intendedto restrict or abort symptomatic attack when it occurs, for exampleanti-inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylacticbenefit in asthma may in particular be apparent in subjects prone to“morning dipping”. “Morning dipping” is a recognised asthmatic syndrome,common to a substantial percentage of asthmatics and characterised byasthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant form any previously administeredsymptomatic asthma therapy.

Other inflammatory or obstructive airways diseases and conditions towhich the present invention is applicable include acute lung injury(ALI), acute/adult respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy. The invention isalso applicable to the treatment of bronchitis of whatever type orgenesis including, e.g., acute, arachidic, catarrhal, croupus, chronicor phthinoid bronchitis. Further inflammatory or obstructive airwaysdiseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

Having regard to their anti-inflammatory activity, in particular inrelation to inhibition of eosinophil activation, agents of the inventionare also useful in the treatment of eosinophil related disorders, e.g.eosinophilia, in particular eosinophil related disorders of the airways(e.g. involving morbid eosinophilic infiltration of pulmonary tissues)including hypereosinophilia as it effects the airways and/or lungs aswell as, for example, eosinophil-related disorders of the airwaysconsequential or concomitant to Löffler's syndrome, eosinophilicpneumonia, parasitic (in particular metazoan) infestation (includingtropical eosinophilia), bronchopulmonary aspergillosis, polyarteritisnodosa (including Churg-Strauss syndrome), eosinophilic granuloma andeosinophil-related disorders affecting the airways occasioned bydrug-reaction.

Agents of the invention are also useful in the treatment of inflammatoryor allergic conditions of the skin, for example psoriasis, contactdermatitis, atopic dermatitis, alopecia areata, erythema multiforma,dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivityangiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus,epidermolysis bullosa acquisita, and other inflammatory or allergicconditions of the skin. Agents of the invention may also be used for thetreatment of other diseases or conditions, in particular diseases orconditions having an inflammatory component, for example, treatment ofdiseases and conditions of the eye such as conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, diseasesaffecting the nose including allergic rhinitis, e.g. atrophic, chronic,or seasonal rhinitis, inflammatory conditions of the gastrointestinaltract, for example inflammatory bowel disease such as ulcerative colitisand Crohn's disease, diseases of the bone and joints includingrheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis andsystemic sclerosis, and other diseases such as atherosclerosis, multiplesclerosis, diabetes (type I), myasthenia gravis, hyper IgE syndrome andacute and chronic allograft rejection, e.g. following transplantation ofheart, kidney, liver, lung or bone marrow.

The effectiveness of an agent of the invention in inhibitinginflammatory conditions, for example in inflammatory airways diseases,may be demonstrated in an animal model, e.g. a mouse or rat model, ofairways inflammation or other inflammatory conditions, for example asdescribed by Szarka et al, J. Immunol. Methods (1997) 202:49-57; Renziet al, Am. Rev. Respir. Dis. (1993) 148:932-939; Tsuyuki et al., J. CliNInvest. (1995) 96:2924-2931; and Cernadas et al (1999) Am. J. Respir.Cell Mol. Biol. 20:1-8.

The agents of the invention are also useful as co-therapeutic agents foruse in combination with other drug substances such as anti-inflammatory,bronchodilatory or antihistamine drug substances, particularly in thetreatment of obstructive or inflammatory airways diseases such as thosementioned hereinbefore, for example as potentiators of therapeuticactivity of such drugs or as a means of reducing required dosaging orpotential side effects of such drugs. An agent of the invention may bemixed with the other drug substance in a fixed pharmaceuticalcomposition or it may be administered separately, before, simultaneouslywith or after the other drug substance. Such anti-inflammatory drugsinclude steroids, in particular gluco-corticosteroids such asbudesonide, beclamethasone, fluticasone, ciclesonide or mometasone, LTB4antagonists such as those described in U.S. Pat. No. 5,451,700, LTD4antagonists such as montelukast and zafirlukast, dopamine receptoragonists such as cabergoline, bromocriptine, ropinirole and4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl]-2(3H)-benzothiazoloneand pharmaceutically acceptable salts thereof (the hydrochloride beingViozan®-AstraZeneca), and PDE4 inhibitors such as Ariflo® (GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer),SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma) andPD189659 (Parke-Davis). Such bronchodilatory drugs includeanticholinergic or antimuscarinic agents, in particular ipratropiumbromide, oxitropium bromide and tiotropium bromide, and beta-2adrenoceptor agonists such as salbutamol, terbutaline, salmeterol and,especially, formoterol and pharmaceutically acceptable salts thereof,and compounds (in free or salt or solvate form) of formula I of PCTInternational Publication No. WO 00/75114, which document isincorporated herein by reference, preferably compounds of the Examplesthereof, especially a compound of formula

and pharmaceutically acceptable salts thereof. Co-therapeuticantihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride.Combinations of agents of the invention and steroids, beta-2 agonists,PDE4 inhibitors or LTD4 antagonists may be used, for example, in thetreatment of COPD or, particularly, asthma. Combinations of agents ofthe invention and anticholinergic or antimuscarinic agents, PDE4inhibitors, dopamine receptor agonists or LTB4 antagonists may be used,for example, in the treatment of asthma or, particularly, COPD.

Other useful combinations of agents of the invention withanti-inflammatory drugs are those with other antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770), CCR-5 antagonists described in U.S. Pat. No.6,166,037 (particularly claims 18 and 19), WO 00/66558 (particularlyclaim 8), and WO 00/66559 (particularly claim 9).

In accordance with the foregoing, the invention also provides a methodfor the treatment of a condition mediated by CCR-3, for example aninflammatory or allergic condition, particularly an inflammatory orobstructive airways disease, which comprises administering to a subject,particularly a human subject, in need thereof an effective amount of acompound of formula I in a free or pharmaceutically acceptable salt formas hereinbefore described. In another aspect the invention provides theuse of a compound of formula I, in free or pharmaceutically acceptablesalt form, as hereinbefore described for the manufacture of a medicamentfor the treatment of a condition mediated by CCR-3, for example aninflammatory or allergic condition, particularly an inflammatory orobstructive airways disease.

The agents of the invention may be administered by any appropriateroute, e.g. orally, for example in the form of a tablet or capsule;parenterally, for example intravenously; by inhalation, for example inthe treatment of inflammatory or obstructive airways disease;intranasally, for example in the treatment of allergic rhinitis;topically to the skin, for example in the treatment of atopicdermatitis; or rectally, for example in the treatment of inflammatorybowel disease.

In a further aspect, the invention also provides a pharmaceuticalcomposition comprising as active ingredient a compound of formula I infree or pharmaceutically acceptable salt form, optionally together witha pharmaceutically acceptable diluent or carrier therefor. Thecomposition may contain a co-therapeutic agent such as ananti-inflammatory bronchodilatory or antihistamine drug as hereinbeforedescribed. Such compositions may be prepared using conventional diluentsor excipients and techniques known in the galenic art. Thus oral dosageforms may include tablets and capsules. Formulations for topicaladministration may take the form of creams, ointments, gels ortransdermal delivery systems, e.g. patches. Compositions for inhalationmay comprise aerosol or other atomizable formulations or dry powderformulations.

When the composition comprises an aerosol formulation, it preferablycontains, for example, a hydro-fluoro-alkane (HFA) propellant such asHFA134a or HFA227 or a mixture of these, and may contain one or moreco-solvents known in the art such as ethanol (up to 20% by weight),and/or one or more surfactants such as oleic acid or sorbitan trioleate,and/or one or more bulking agents such as lactose. When the compositioncomprises a dry powder formulation, it preferably contains, for example,the compound of formula I having a particle diameter up to 10 microns,optionally together with a diluent or carrier, such as lactose, of thedesired particle size distribution and a compound that helps to protectagainst product performance deterioration due to moisture. When thecomposition comprises a nebulised formulation, it preferably contains,for example, the compound of formula I either dissolved, or suspended,in a vehicle containing water, a co-solvent such as ethanol or propyleneglycol and a stabiliser, which may be a surfactant.

The invention includes (A) an agent of the invention in inhalable form,e.g. in an aerosol or other atomisable composition or in inhalableparticulate, e.g. micronised form, (B) an inhalable medicamentcomprising an agent of the invention in inhalable form; (C) apharmaceutical product comprising such an agent of the invention ininhalable form in association with an inhalation device; and (D) aninhalation device containing an agent of the invention in inhalableform.

Dosages of agents of the invention employed in practising the presentinvention will of course vary depending, for example, on the particularcondition to be treated, the effect desired and the mode ofadministration. In general, suitable daily dosages for administration byinhalation are of the order of 0.01 to 30 mg/kg while for oraladministration suitable daily doses are of the order of 0.01 to 100mg/kg.

The invention is illustrated by the following Examples.

EXAMPLES 1-19

Compounds of formula II are shown in the following table, the methods ofpreparation being described hereinafter. The table also showscharacterising mass spectrometry data. X is O except in Example 7 whereit is C═O. The value of m in formula II is 2. The compounds are all infree form.

MS Ex. Ar R¹ R³ [M + H] 1

505.3 2

449.1 3

4

H

414.1 5

H

380.1 6

H

386.1 7

H

405.0 8

H

399.1 9

H

393.1 10

H

401.1 11

H

421.1 12

H

369.1 13

H

380.0 14

681.4 15

607.3 16

H

442.2 17

431.2 18

428.8 19

H

412.5[M+]

EXAMPLES 20-57

Compounds of formula III are shown in the following table, the methodsof preparation being described hereinafter. The table also showscharacterising mass spectrometry data. X is O except in Examples 34, 37and 49, where it is C═O. R² is hydrogen except in Example 54 where it isCH₃, and in Example 55 where R² and R³ together with the attachednitrogen atom denote the group shown in the R³ column. The value of m informula III is 2 for Examples 20-56 and 3 for Example 57. Examples24-25, 27, 29-33 and 36 are in the form of the trifluoroacetate salt;the others are in free form.

MS [M + Ex. Ar R¹ R³ H] 20

H

404.1 21

CH₂OH

434.1 22

H

362.1 23

H

380.1 24

H

422.1 25

H

402.2 26

CH₂OH

450.0 27

H

372.2 28

CH₂OH

426.2 29

CH₂OH

420.2 30

H

372.2 31

CH₂OH

458.2 32

CH₂OH

408.2 33

CH₂OH

438.2 34

CH₂OH

446.1 35

CH₂OH

484.0 36

H

386.1 37

CH₂OH

461.8 38

CH₂OH

423.6 39

CH₂OH

417.5 40

CH₂OH

431.7 41

CH₂OH

418.0 42

CH₂OH

429.9 43

H

360.1 44

CH₂OH

418.0 45

CH₂OH

403.6 46

CH₂OH

419.8 47

CH₂OH

425.5 48

CH₂OH

449.9 49

CH₂OH

495.6 50

CH₂OH

417.8 51

CH₂OH

425.7 52

CH₂OH

464.2 53

H

420.1 54

H

364.0 55

H

384.1 56

H

374.0 57

H

417.5

EXAMPLES 58-65

Compounds of formula IV are shown in the following table, the methods ofpreparation being described hereinafter. The table also showscharacterising melting point and/or mass spectrometry data. The value ofm in formula IV is 2 in all of these Examples, R¹ is hydrogen and X isO. The compounds are all in free form.

MS Ex. Ar R³ [M + H] 58

390.0 59

383.0 60

379.0 61

415.1 62

365.0 63

440.7 64

457.37 65

415.49

EXAMPLES 66 to 128

Compounds of formula III where R² is hydrogen and m is 2 are shown inthe following table, the methods of preparation being describedhereinafter. The table also shows characterising melting point and/ormass spectrometry data. Examples 77 and 92 are in the form of thetrifluoroacetate salt, the others are in free form.

MS [M + Ex. Ar X R¹ R³ H] 66

—O—

448.4 67

—O—

438.3 68

—O— —H

396.2 69

—CH₂—

446.34 70

—CH₂—

421.3 71

—CH₂—

408.3 72

—CH₂—

407.3 73

—CH₂—

432.4 74

—CH₂—

424.3 75

—O—

448.3 76

—O—

423.3 77

—O—

440.3 78

—O—

436.4 79

—O—

450.4 80

—CH₂—

462.3 81

—O—

437.3 82

—O—

395.2 83

—O—

434.3 84

—O—

423.3 85

—O—

412.3 86

—O—

440.3 87

—O—

396.3 88

—O—

422.3 89

—O—

424.3 90

438.3 91

—O—

410.3 92

—O—

409.3 93

—O—

440.3 94

—O—

460.2 95

—O—

411.2 96

—O—

415.3 97

—O—

461.2 98

—O—

414.2 99

—O—

426.2 100

—O—

412.2 101

—O—

390.2 102

—O—

475.2 103

—O—

469.2 104

—O—

509.2 105

—CH₂—

448.1 106

—O—

450.1 107

—O—

441.1 108

—O—

434.1 109

—O—

395.1 110

—O—

391.1 111

—O—

447.1 112

—O—

432.1 113

—O—

447.0 114

430.1 115

—O—

448.1 116

—O—

464.1 117

—O—

468.0 118

—O—

433.0 119

—O—

461.1 120

444.1 121

—O—

472.4 122

—O—

492.1 123

—O—

437.9 124

—O—

468.0 125

—O—

425.2 126

—O—

390.9 127

—O—

472.4 128

—O—

437.9

EXAMPLES 129 to 203

Compounds of Formula IIIa

where m is 2 (except for Ex. 129 where m is 1) are shown in thefollowing table, the methods of preparation being described hereinafter.The table also shows characterising melting point and/or massspectrometry data. All compounds are in free form.

MS Ex. Ar X R¹ Y R² R³ [M + H] 129

—O—

O H

412.3 130

—O—

O —CH₃

463.5 131

—O—

S H

435.6 132

—O—

S H

411.5 133

—O—

S H

436.2 134

—O—

O H

468.2 135

—O—

O H

— 136

—O—

O H

— 137

—O—

O H

— 138

—O—

O H

456.2 139

—O—

O H

— 140

—O—

O H

— 141

—O—

O H

— 142

—O—

O H

— 143

—O—

O H

— 144

—O—

O H

— 145

—CH₂—

O H

— 146

—CH₂—

O H

— 147

—CH₂—

O H

— 148

—CH₂—

O H

— 149

—CH₂—

O H

— 150

—CH₂—

O H

— 151

—CH₂—

O H

— 152

—CH₂—

O H

— 153

—CH₂—

O H

— 154

—CH₂—

O H

— 155

—CH₂—

O H

— 156

—CH₂—

O H

— 157

—CH₂—

O H

— 158

—CH₂—

O H

— 159

—CH₂—

O H

— 160

O H

— 161

O H

— 162

O H

— 163

O H

— 164

O H

— 165

O H

— 166

O H

— 167

O H

— 168

O H

— 169

—O—

O H

392.2 170

—O—

O H

426.2 171

—O—

O H

— 172

—O—

O H

— 173

—O—

O H

— 174

—CH₂—

O H

— 175

—CH₂—

O H

— 176

O H

— 177

O H

— 178

—O—

O H

— 179

—O—

O H

— 180

—CH₂—

O H

— 181

—CH₂—

O H

— 182

O H

— 183

O H

— 184

—O—

O H

— 185

—O—

O H

— 186

—CH₂—

O H

— 187

—CH₂—

O H

— 188

O H

— 189

O H

— 190

—CH₂— H O H

394.1 191

—CH₂— —CH₃ O H

394.1 192

—O—

O H

409.2 193

—O—

O H

450.2 194

—O—

O H

436.2 195

—O—

O H

464.3 196

—O—

O H

410.2 197

—O—

O H

410.2 198

—O—

O H

— 199

—O—

O H

— 200

—O— H O H

410.2 201

—O— H O H

430.1 202

—O—

O H

409.2 203

—O—

O H

382.3Preparation of Starting Compounds

(S)-2-Amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol

A solution of{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-carbamicacid tert-butyl ester. (0.46 g, 1.24 mmol) in dichloromethane (6 ml) istreated with trifluoroacetic acid (2 ml) and the reaction mixturestirred for 1 hour at ambient temperature. The solvent is evaporated andthe residue dissolved in water. The resulting aqueous solution isbasified with saturated aqueous NaHCO₃ and extracted intodichloromethane. The dichloromethane is dried over MgSO₄ and evaporatedto afford (S)-2-amino-4-[3-(4-chlorophenoxy)-azetidin-1-yl]-butan-1-olas a clear oil. [MH]+ 271.0

{1-[(S)-3-Amino-4-(tert-butyl-diphenyl-silanyloxy)-butyl]-azetidin-3-yl}-(4-fluoro-phenyl)-methanone

A solution of{(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-propyl}-carbamicacid tert-butyl ester. (0.188 g, 0.321 mmol) in dichloromethane (5 ml)is treated with trifluoroacetic acid, and stirred at ambient temperaturefor 0.5 hour. The reaction mixture is diluted with dichloromethane andwashed with water and saturated aqueous NaHCO₃. The organic phase isdried over MgSO₄ and evaporated to afford{1-[(S)-3-Amino-4-(tert-butyl-diphenyl-silanyloxy)-butyl]-azetidin-3-yl)-(4-fluoro-phenyl)-methanone.[MH]+ 505.2.

Azetidin-3-yl-(4-chloro-phenyl)-methanone hydrochloride

A solution of (1-Benzhydryl-azetidin-3-yl)-(4-chloro-phenyl)-methanone(19.8 g, 54.8 mmol) in dichloromethane (250 ml), cooled to −4° C., istreated with 1-chloroethylchloroformate (8.0 ml, 73.8 mmol) and allowedto warm to ambient temperature. The reaction mixture is stirred for 18hours and then evaporated. The residue is dissolved in methanol (220 ml)and stirred at ambient temperature for 3.5 hours. The methanol solutionis concentrated and the product precipitated by addition ofdiethylether. The precipitate is collected by filtration and dries underhigh vacuum to afford Azetidin-3-yl-(4-chloro-phenyl)-methanonehydrochloride. [MH]+ 195.95.

Other substituted benzoyl azetidine compounds are made analogously.

(1-Benzhydryl-azetidin-3-yl)-(4-chloro-phenyl)-methanone

A solution of 1-Benzhydryl-azetidine-3-carbonitrile (23.6 g, 95 mmol) inchlorobenzene (250 ml) under nitrogen is treated with a 1.0 M solutionof 4-chlorophenylmagnesium bromide in diethylether (100 ml, 100 mmol)over one hour, ensuring the temperature does not exceed 30° C. Thestirred reaction mixture is heated to 60° C. for 1 hour, then cooledback to ambient temperature and quenched with a saturated aqueoussolution of ammonium chloride (250 ml). The organic phase is washed withbrine, dried over magnesium sulphate, and evaporated to a yellow oil.The oil is dissolved in methanol (300 ml), treated with concentratedhydrochloric acid (25 ml), and stirred at ambient temperature for 18hours. The solvent is evaporated and the residue partitioned betweenethylacetate (250 ml) and saturated sodium bicarbonate solution (250ml). The aqueous phase is extracted with more ethylacetate and thecombined organic phases, treated with magnesium sulphate and charcoal,filtered and evaporated to afford(1-Benzhydryl-azetidin-3-yl)-(4-chloro-phenyl)-methanone. [MH]+ 361.99

1-Benzhydryl-3-(3,4-dichloro-phenoxy)-azetidine

A solution of 3,4 dichlorophenol (4.12 g, 25.3 mmol) in DMF (150 ml)under argon is treated with a 60% dispersion of sodium hydride inmineral oil (40.4 mmol) and the reaction mixture stirred for 10 minutes.A solution of Methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester(7.27 g, 22.96 mmol) in DMF (50 ml) is added and the reaction mixtureleft to stir at 60° C. for 20 hours. The reaction mixture is partitionedbetween ethylacetate and water. The organic phase is washed with water(×2), dried over magnesium sulphate and evaporated. The crude product ispurified by flash silica chromatography (elution with 1:4ethylacetate/isohexane) to afford1-Benzhydryl-3-(3,4-dichloro-phenoxy)-azetidine. [M+H] 383.8

N-(3-Bromo-propyl)-3-cyano-benzenesulfonamide

A suspension of bromopropylamine hydrogen bromide (0.219 g, 1 mmol) indichloromethane (2 ml) is treated with a solution ofdimethylaminopyridine (0.004 g) in dichloromethane (0.5 ml) followed bya solution of 3-cyano-benzenesulfonyl chloride (0.2 g, 1.0 mmol) indichloromethane (0.5 ml). Triethylamine (0.3 ml, 2.16 mmol) is added andthe reaction mixture stirred at ambient temperature for 2 hours, thenquenched with water and saturated aqueous NaHCO₃, and extracted intodichloromethane. The organic phase is washed with aqueous 1M HClsolution and brine, dried over MgSO₄ and evaporated to afford crudeN-(3-bromopropyl)-3-cyano-benzenesulfonamide. (¹³C NMR, 100 MHz, CDCl₃,30.2, 32.6, 41.9, 114.3, 117.5, 130.7, 130.9, 131.1, 136.3, 142.1).

(S)-2-tert-Butoxycarbonylamino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-4-oxo-butyricacid benzyl ester

A solution of (S)-2-tert-butoxycarbonylamino-succinic acid 1-benzylester (5.0 g, 13.99 mmol) in dichloromethane (50 ml) is treated withdiisopropylethylamine (7.51 ml, 41.97 mmol) and2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate(4.49 g, 13.99 mmol). To the reaction mixture is added3-(4-chloro-phenoxy)-azetidine hydrochloride (3.06 g, 13.99 mmol) andstirring continued for 3 hours. The dichloromethane is evaporated andresidue partitioned between ethylacetate and saturated NaHCO₃ solution.The ethylacetate phase is washed with 1M HCl solution and brine, driedover MgSO₄ and evaporated. The crude product is purified by flash silicachromatography (elution with 1:1 ethylacetate/hexane) to afford(S)-2-tert-butoxycarbonylamino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]4-oxo-butyricacid benzyl ester. [M-BOC] 389.0.

(S)-3-tert-Butoxycarbonylamino-4-iodo-butyric acid benzyl ester

A suspension of polymer bound triphenyl phosphine (18.25 g, 54.76 mmol)in DCM (100 ml) is treated with iodine (12.2 g, 48.1 mmol) and thereaction mixture stirred at ambient temperature for 15 minutes.Imidazole (3.72 g, 54.7 mmol) is added and the reaction mixture stirredfor a further 15 minutes. A solution of(S)-3-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (6.76g, 21.9 mmol) in DCM (100 ml) is added. The suspension is stirred atreflux for 1.5 hours, then filtered through Celite™ filter material,washing through with DCM. The combined organic phase is washed with anaqueous solution of 10% sodium thiosulphate, water and brine, then driedover magnesium sulphate and evaporated. The crude product ischromatographed over flash silica using 8% ethylacetate in iso-hexane aseluent to afford (S)-3-tert-butoxycarbonylamino-4-iodo-butyric acidbenzyl ester. [M-BOC] 320.12

(S)-3-tert-Butoxycarbonylamino-4-methoxy-butyric acid benzyl ester

A solution of (S)-3-tert-butoxycarbonylamino-4-hydroxy-butyric acidbenzyl ester (31.4 g, 101 mmol) (prepared using the method of Rodriguez,Marc; Linares, Muriel; Doulut, Sylvie; Heitz, Annie; Martinez, Jean;Tetrahedron Lett. (1991), 32(7), 923-6) in dichloromethane (280 ml) iscooled to −20° C. and a 48% aqueous solution of tetrafluoroboric acid(13.3 ml, 101 mmol) added. With vigorous stirring is added dropwise a2.0 M solution of trimethylsilyl-diazomethane (50.8 ml, 101 mmol) inhexane over 35 minutes. After stirring for a further 30 minutes, asecond aliquot of trimethylsilyldiazomethane is added (12.7 ml, 25 mmol)slowly over 10 minutes. After stirring for a further 30 minutes at −20°C. a further aliquot of trimethylsilyl-diazomethane (12.7 ml, 25 mmol)is added over 10 minutes. This pattern is continued until a total of 127ml of trimethylsilyldiazomethane solution (254 mmol) is added. After thelast addition the reaction mixture is left to stir for 1.5 hours at −20°C. The reaction mixture is then quenched with water and extracted intodichloromethane. The organic phase is dried over magnesium sulphate andevaporated. The crude product is purified by flash silica chromatography(elution with 2:8 ethylacetate/hexane) to afford(S)-3-tert-Butoxycarbonyl-amino-4-methoxy-butyric acid benzyl ester as aclear oil. [M-BOC] 224.19.

(S)-3-tert-Butoxycarbonylamino-4-(tert-butyl-diphenyl-silanyloxy)-butyricacid benzyl ester

A solution of (S)-3-tert-butoxycarbonylamino-4-hydroxy-butyric acidbenzyl ester (1.34 g, 4.37 mmol) (prepared using the method ofRodriguez, Marc; Linares, Muriel; Doulut, Sylvie; Heitz, Annie;Martinez, Jean; Tetrahedron Lett. (1991), 32(7), 923-6) and imidazole(0.88 g, 13.01 mmol in dimethylformamide (7 ml) is treated withtertbutyldiphenylsilyl chloride (1.69 ml, 6.5 mmol). The reactionmixture is stirred together at room temperature for 1 hour, then dilutedwith water and extracted into ethylacetate. The ethylacetate phase isdried over MgSO₄ and evaporated. The crude product is purified by flashsilica chromatography (elution with 1:1 ethylacetate/hexane) to afford(S)-3-tert-butoxycarbonylamino-4-(tert-butyl-diphenyl-silanyloxy)-butyricacid benzyl ester. [M-BOC] 448.0.

(S)-1-tert-Butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine

A solution of{(S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-carbamicacid benzyl ester (0.2 g, 0.45 mmol) in methanol containing 10%palladium on carbon (66 mg) is stirred under an atmosphere of hydrogenfor 3 hours, then filtered through a celite™ filter The filtrate isevaporated and the residue taken up in ethyl acetate, washed withaqueous NaHCO₃ solution and brine, dried over MgSO₄ and evaporated toafford(S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine.

{(S)-1-(tert-Butyl-diphenyl-silanyloxymethyl)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl-]-propyl}-carbamicacid tert-butyl ester

A solution of 4-fluorobenzoyl-azetidine hydrochloride (0.192 g, 0.892mmol), triethylamine (0.252 ml, 3.24 mmol) and[(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-iodo-propyl]-carbamicacid tert-butyl ester (0.448 g, 0.811 mmol) in dimethylformamide (3 ml)is stirred at ambient temperature for 18 hours, then partitioned betweenethylacetate and water. The ethylacetate phase is dried over MgSO₄ andevaporated. The crude product is purified by flash silica chromatography(elution with a 1:99 methanol/dichloromethane) to afford{(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-propyl}carbamicacid tert-butyl ester. [MH]+ 605.2.

1-{(S)-1-(tert-Butyl-diphenyl-silanyloxymethyl)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl-propyl}-3-(3,5-dimethoxy-phenyl)-urea

A solution of1-[(S)-3-amino-4-(tert-butyl-diphenyl-silanyloxy)-butyl]-azetidin-3-yl}-(4-fluorophenyl)-methanone(0.152 g, 0.301 mmol) and 3,5-dimethoxyphenylisocyanate (0.054 g, 0.301mmol) in dichloromethane (3 ml) is stirred at ambient temperature for 18hours. The solvent is evaporated and the crude product purified by flashsilica chromatography (elution with a 2:98 methanol/dichloromethane) toafford1-{(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-propyl}-3-(3,5-dimethoxy-phenyl)-urea.[MH]+ 684.1.

[(S)-1-(tert-Butyl-diphenyl-silanyloxymethyl)-3-hydroxy-propyl]-carbamicacid tert-butyl ester

A solution of(S)-3-tert-butoxycarbonylamino-4-(tert-butyl-diphenyl-silanyloxy)-butyricacid benzyl ester in (2.37 g, 4.33 mmol) in dry diethylether (25 ml) at0° C. is treated with a 2 M solution of lithium borohydride in THF (4.33ml). The reaction mixture is allowed to warm to ambient temperature andstirred for 3 hours under argon, then quenched by addition of water (10ml) and 0.5 M aqueous citric acid solution (20 ml). The ether isseparated, and the aqueous phase extracted with more ether. The combinedether phases are dried over MgSO₄ and evaporated. The crude product ispurified by flash silica chromatography on a biotage column (90 g)(elution with a 1:3 ethylacetate/hexane then methanol) to afford[(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-hydroxy-propyl]-carbamicacid tert-butyl ester [M-BOC] 344.1.

[(S)-1-(tert-Butyl-diphenyl-silanyloxymethyl)-3-iodo-propyl]-carbamicacid tert-butyl ester

A suspension of polystyrene resin-bound triphenylphosphine (2.33 g, 3mmol/g in dry dichloromethane (25 ml) is treated with iodine (1.56 g,6.16 mmol) and stirred for 15 minutes under argon. Imidazole (0.477 g,7.0 mmol) is added and the reaction mixture stirred at room temperaturefor a further 15 minutes. The reaction mixture is then treated with asolution of[(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-hydroxy-propyl]carbamicacid tert-butyl ester (1.24 g, 2.8 mmol) in dichloromethane (5 ml). Thereaction mixture is refluxed for 2 hours under argon, then filteredthrough a Celite™ filter pad, washing with dichloromethane. The filtrateis washed with 5% aqueous sodium thiosulphate solution and water, driedover MgSO₄ and evaporated. The crude product is purified by flash silicachromatography (elution with 1:99 methanol/dichloromethane) to afford[(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-iodo-propyl]-carbamicacid tert-butyl ester. [M-BOC] 453.9.

3-(4-Chloro-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester

A solution of azetidin-3-yl-(4-chloro-phenyl)-methanone hydrochloride(50 g, 210 mmol) in dioxan:water 1:1 (800 ml) is added powdered sodiumbicarbonate (61.7 g, 730 mmol) and the reaction mixture cooled to 10° C.Di-tbutyl-dicarbonate (52.6 g, 240 mmol) is added portion wise and thereaction mixture allowed to warm to room temperature with stirring for1.5 hours. The reaction mixture is poured into water (1500 ml) and theresulting white precipitate filtered off and dried under vacuum toafford 3-(4-Chloro-benzoyl)-azetidine-1-carboxylic acid tert-butylester. ¹H NMR 400 MHz, CDCl₃, δ 1.45 (9H), 4.10 (1H), 4.20 (4H), 7.47(2H), 7.80 (2H)

3-(4-Chloro-benzyl)-azetidine-1-carboxylic acid tert-butyl ester

A solution of 3-[(4-Chloro-phenyl)-iodo-methyl]-azetidine-1-carboxylicacid tert-butyl ester (58 g, 140 mmol) in dimethylsulphoxide (450 ml) istreated with sodium borohydride with cooling. The reaction mixture wasstirred at room temperature for 20 hours, then quenched by the slowaddition of water (1000 ml). The aqueous mixture is extracted intoethylacetate, and the ethylacetate phase washed with saturated brine,dried over magnesium sulphate and evaporated. The crude product ispurified by flash chromatography using a biotage 75 column (eluantgradient isohexane:ethylacetate 9:1 to 85:15) to afford3-(4-Chloro-benzyl)-azetidine-1-carboxylic acid tert-butyl ester. ¹H NMR400 MHz, CDCl₃, δ 1.35 (9H), 2.70 (1H), 2.80 (2H), 3.55 (2H), 3.90 (2H),6.97 (2H), 7.17 (2H).

{3-[3-(4-Chloro-benzyl)-azetidin-1-yl]-propyl}-carbamic acid tert-butylester

A solution of 3-(4-chloro-benzyl)-azetidine (1.0 g, 5.50 mmol),(3-bromo-propyl)-carbamic acid tert-butyl ester (1.31 g, 5.50 mmol) anddiisopropylethylamine (1.91 ml, 11.0 mmol) in dry dimethylformamide (20ml) is stirred at ambient temperature for 18 hours. The reaction mixtureis partitioned between ethylacetate and water. The organic phase iswashed with water and brine, dried over magnesium sulphate andevaporated. The crude product is purified by flash silica chromatographyusing 5% methanol in dichloromethane as eluent to afford{3-[3-(4-Chloro-benzyl)-azetidin-1-yl]-propyl]-carbamic acid tert-butylester. [M+H] 339.15

3-[3-(4-Chloro-benzyl)-azetidin-1-yl]-propylamine

A solution of {3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propyl}-carbamicacid tert-butyl ester (0.48 g, 1.43 mmol) in DCM (5 ml) is treated withtrifluoroacetic acid (2 ml) and the reaction mixture stirred for 1.25hours. The solvent is evaporated and the crude product partitionedbetween 1 M sodium hydroxide solution and 20% isopropanol in DCM. Theorganic phase is evaporated to afford3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propylamine. [M+H] 239.13.

3-(4-Chloro-benzyl)-azetidinium trifluoroacetate salt

A solution of 3-(4-Chloro-benzyl)-azetidine-1-carboxylic acid tert-butylester (1.61 g, 5.71 mmol) in dichloromethane (20 ml) is treated withtrifluoroacetic acid (20 ml) and stirred at ambient temperature for 1hour. The reaction mixture is evaporated and then re-suspended intoluene and evaporated to dryness to afford3-(4-Chloro-benzyl)-azetidinium trifluoroacetate salt. [MH]+ of freebase 182.12.

All other substituted benzyl azetidine compounds are made analogously.

{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-carbamicacid tert-butyl ester

A solution of(S)-2-tert-butoxycarbonylamino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]4-oxo-butyricacid benzyl ester (1.0 g, 2.04 mmol) in dry THF (10 ml) is treated witha 1M solution of lithium aluminium hydride (5.1 ml) keeping thetemperature between 20-30° C. using an ice-water bath. The reactionmixture is stirred at ambient temperature under argon for 2 hours, thenquenched by addition of saturated aqueous Na₂SO₄ and filtered through acelite™ filter. The filtrate is partitioned between ethylacetate andsaturated brine. The ethylacetate phase dried over MgSO₄ and evaporated.The crude product is purified by flash silica chromatography (elutionwith 5:95 methanol/dichloromethane) to afford{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-carbamicacid tert-butyl ester. [MH]+ 371.0.

(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propyl}-carbamicacid tert-butyl ester

A solution of 3-(4-Chloro-phenoxy)-azetidine hydrochloride (0.669 g,3.04 mmol), triethylamine (1.7 ml, 12.16 mmol) and[(S)-3-Iodo-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester (1.0g, 3.04 mmol) in dimethylformamide (10 ml) is stirred at ambienttemperature for 18 hours, then partitioned between ethylacetate andwater. The ethylacetate phase is washed with saturated aqueous sodiumbicarbonate solution and brine, dried over MgSO₄ and evaporated. Thecrude product is purified by flash silica chromatography (elution with a5:95 methanol/dichloromethane) to afford{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propyl}-carbamicacid tert-butyl ester as a clear oil. [MH]+ 385.25.

(S)-3-[3-(Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propylamine

A solution of{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propyl}-carbamicacid tert-butyl ester (0.87 g, 2.26 mmol) in dichloromethane (7 ml) istreated with trifluoroacetic acid (2 ml), and stirred at ambienttemperature for 18 hours. The solvent is evaporated and the residuetaken up in water, made alkali with 4.0 M aqueous sodium hydroxidesolution and extracted into dichloromethane. The organic phase is driedover MgSO₄ and evaporated to afford(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propylamine.[MH]+ 285.20

{(R)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-carbamicacid tert-butyl ester

A solution of ((R)-3-iodo-1-methyl-propyl)-carbamic acid tert-butylester (0.038 mg, 0.13 mmol), 3-(4-chloro-phenoxy)-azetidinehydrochloride (0.030 g, 0.13 mmol) and triethylamine (0.073 ml, 0.52mmol) in DMF (1 ml) is stirred at room temperature for 18 hours. Thereaction mixture is partitioned between ethylacetate and a saturatedsolution of sodium bicarbonate. The organic phase is washed with waterand brine, dried over magnesium sulphate and evaporated. The crudeproduct is purified by flash silica chromatography using 1:1ethylacetate:hexane as eluent to afford{(R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-carbamicacid tert-butyl ester. [M+H] 355.33

(R)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methyl-propylamine

A solution of{(R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-carbamicacid tert-butyl ester (0.019 mg, 0.053 mmol) in DCM (1 ml) is treatedwith trifluoroacetic acid (0.042 ml) and stirred at room temperatureovernight. The solvent is evaporated and the residue partition betweenDCM and 1M sodium hydroxide solution. The aqueous phase is extractedwith more DCM (×3) and the combined organic phases washed with brine,dried over magnesium sulphate and evaporated to afford(R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propylamine. [M+H]255.22

3-[(4-Chloro-phenyl)-hydroxy-methyl]-azetidine-1-carboxylic acidtert-butyl ester

A solution of 3-(4-Chloro-benzoyl)-azetidine-1-carboxylic acidtert-butyl ester (62.5 g, 210 mmol) in ethanol (1000 ml) cooled to 10°C. is treated with sodium borohydride (9.5 g, 250 mmol). The reactionmixture is allowed to warm to room temperature and stirred for 2 hours.The reaction mixture is added to water and the precipitate collected byfiltration, and dried under vacuum to afford3-[(4-Chloro-phenyl)-hydroxy-methyl]-azetidine-1-carboxylic acidtert-butyl ester. Mpt 123-125° C.

3-[(4-Chloro-phenyl)-iodo-methyl]-azetidine-1-carboxylic acid tert-butylester

Polymer supported triphenylphosphine (125 g, 370 mmol) is suspended intetrahydrofuran: acetonitrile 9:1 (1000 ml) and treated with Iodine(95.2 g, 370 mmol) followed by stirring for 15 minutes. Imidazole (25.5g, 370 mmol) is added followed by a solution of3-[(4-Chloro-phenyl)-hydroxy-methyl]-azetidine-1-carboxylic acidtert-butyl ester (44.7 g, 150 mmol) in tetrahydrofuran (150 ml) and thereaction mixture stirred at ambient temperature for 20 hours. Thereaction mixture is filtered through celite™ filter material and thefiltrate evaporated. The residue is taken up in chloroform and washedwith sodium thiosulphate solution, water and brine. The solution isdried over magnesium sulphate and evaporated to provide3-[(4-Chlorophenyl)-iodo-methyl]-azetidine-1-carboxylic acid tert-butylester. ¹H NMR 400 MHz, CDCl₃, δ 1.35 (9H), 3.21 (1H), 3.37 (1H), 3.60(2H), 4.05 (1H), 5.12 (1H), 7.20 (4H).

(5-Cyclobutyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester

A solution of 5-Cyclobutyl-2-methyl-2H-pyrazol-3-ylamine (0.156 g, 1.03mmol) in dimethylformamide (3 ml) cooled to 0° C., is treated withphenylchloroformate (0.13 ml, 1.03 mmol) dropwise and left to stir at 0°C. for 1 hour. The reaction mixture is partitioned between ethylacetateand 1.0 M hydrochloric acid solution, and the organic phase washed withwater, dried over magnesium sulphate and evaporated to yield(5-Cyclobutyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester.[M+H] 272.22

(5-Ethyl-2-isopropyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester,(2-tert-Butyl-5-ethyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester and(2,5-Diethyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester are preparedanalogously using appropriate starting materials.

5-Cyclobutyl-2-methyl-2H-pyrazol-3-ylamine

This is synthesized in an analogous manner to5-ethyl-2-methyl-2H-pyrazol-3-ylamine except using3-cyclobutyl-3-oxopropionitrile instead of 3-oxo-pentanenitrile.

(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester

A solution of 5-Cyclopropyl-2-methyl-2H-pyrazol-3-ylamine (3.0 g, 22mmol) (65 ml) and sodium bicarbonate (2 g, 24 mmol) in THF is cooled to0° C. Phenylchloroformate (3.4 g, 22 mmol) is added dropwise over 15minutes. The reaction mixture is allowed to warm to ambient temperatureand stirred for 5 hours, then filtered and the filtrate partitionedbetween ethylacetate and water. The organic phase is washed with water,5% aqueous citric acid solution and brine, dried over MgSO₄ andevaporated to afford (5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-carbamicacid phenyl ester. [M+H] 258.17.

3-(3,4-Dichloro-phenoxy)-azetidine hydrochloride

A solution of 1-Benzhydryl-3-(3,4-dichloro-phenoxy)-azetidine (2.14 g,6.4 mmol) in dry dichloromethane (20 ml) is treated with1-chloroethylchloroformate (0.832 ml, 7.7 mmol) with stirring for 4hours. The solvent is evaporated and the residue dissolved in methanoland refluxed for 18 hrs. The methanol is evaporated to a saturatedsolution, and then treated with diethylether. The resulting precipitateis filtered and dried under vacuum to afford3-(3,4-Dichloro-phenoxy)-azetidine hydrochloride. 1H NMR (D6 DMSO, 400Mhz) δ 9.5 (2H, brS), 7.6 (1H, d), 7.2 (1H, s), 6.9 (1H, d), 5.1 (1H,m), 4.4 (2H, m), 3.95 (2H, m).

All other substituted phenoxy azetidine hydrochloride compounds are madeanalogously.

(3,5-Dimethoxy-phenyl)-methyl-carbamoyl chloride

A solution of phosgene (11.6 mmol) in toluene (6 ml) is diluted withdichloromethane (15 ml) and cooled to 0° C. To this is added a solutionof (3,5-Dimethoxy-phenyl)-methyl-amine (1.67 g, 10 mmol) andtriethylamine (1.78 ml, 14.0 mmol) in dichloromethane (5 ml) slowly over30 minutes, and the reaction mixture allowed to warm to ambienttemperature with stirring over 2 hours. After stirring at ambienttemperature for a further 2 hours, the reaction mixture is partitionedbetween ether and 1M hydrochloric acid solution. The ether phase iswashed with brine, dried over magnesium sulphate and evaporated toafford (3,5-Dimethoxy-phenyl)methyl-carbamoyl chloride as a white solid.

(2-Ethyl-[1,3]dioxolan-2-yl)-acetonitrile

A solution of 3-oxo-pentanenitrile (1.582 g, 16.49 mmol), ethyleneglycol (1.026 ml, 84.59 mmol) and a catalytic amount of p-TolueneSulphonic acid (8 mg) in Toluene (10 ml) is refluxed at 150° C. for 2days using Dean-Stark apparatus. The reaction mixture is diluted withethyl acetate and washed with saturated sodium bicarbonate solution. Theorganic phase is dried over MgSO₄, filtered, and the solvent evaporatedto yield (2-ethyl-[1,3]dioxolan-2-yl)-acetonitrile. 1H NMR (400 MHz,CDCl3) d 4.15(2H,m), 4.05 (2H, m), 2.65 (2H, s), 1.80 (2H, q), 0.95 (3H,t)

2-(2-Ethyl[1,3]dioxolan-2-yl)-N-hydroxy-acetamidine

A solution of NaOH (1.17 g, 29.3 mmol) in water/methanol (1:1) (18 ml),cooled to 0° C. in an ice bath, is treated with hydroxylaminehydrochloride (1.58 g, 22.78 mmol), with stirring for 5 minutes.(2-Ethyl-[1,3]dioxolan-2-yl)-acetonitrile (1.42 g, 10.125 mmol) is addedand the reaction mixture stirred at room temperature for 18 hours, thenrefluxed for a further 2 hours. The reaction mixture is cooled andpartitioned between ethyl acetate and water. The organic phase is driedover MgSO₄, filtered, and the solvent evaporated to yield 2-(2-Ethyl[1,3]dioxolan-2-yl)-N-hydroxy-acetamidine. [M+H] 175.21

5-Ethyl-isoxazol-3-ylamine

A solution of 2-(2-ethyl[1,3]dioxolan-2-yl)-N-hydroxy-acetamidine (1.49g 8.564 mmol) in ethanol (49 ml), acidified to pH 1 with concentratedhydrochloric acid solution, is refluxed at 50° C. for 3 days. Thesolvent is evaporated and the crude product dissolved in water andextracted into ethyl acetate (×2). The organic phase is dried over MgSO₄and evaporated to afford 5-ethyl-isoxazol-3-ylamine. [M+H] 113.02

(5-Ethyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester

A solution of 5-Ethyl-2-methyl-2H-pyrazol-3-ylamine (10 g, 79.8 mmol)(500 ml) and potassium carbonate in THF (12.14 g, 87.8 mmol) is cooledto 0° C. Phenylchloroformate (10.15 ml, 80.6 mmol) is added dropwiseover 20 minutes. The reaction mixture is stirred for 40 minutes at 0° C.then allowed to warm to ambient temperature and stirred for a further2.5 hours. The reaction mixture is partitioned between ethylacetate andwater. The organic phase is washed with 5% aqueous citric acid solutionand brine. The organic phase is treated with MgSO₄ and charcoal thenfiltered and evaporated to afford(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester.[M+H] 246.21

5-Ethyl-2-methyl-2H-pyrazol-3-ylamine

A solution of 3-Oxo-pentanenitrile (0.5 g, 5.15 mmol) andmethylhydrazine (0.24 g, 5.15 mmol) in ethanol (5 ml) is heated toreflux for 1.5 hours. The solvent is evaporated and the residuepartitioned between ethylacetate and brine. The organic phase is driedover MgSO₄ and evaporated to afford5-Ethyl-2-methyl-2H-pyrazol-3-ylamine.

(2-Ethyl-2H-tetrazol-5-yl)-carbamic acid phenyl ester

A solution of 2-ethyl-2H-tetrazol-5-ylamine (0.1 g, 0.88 mmol) in dryTHF (2 ml) is treated with pyridine (0.09 ml, 1.10 mmol) followed by asolution of phenylchloroformate (0.11 ml, 0.911 mmol) in THF (1 ml). Thereaction mixture is stirred at ambient temperature for 1.5 hours, thenpartitioned between ethylacetate and water. The ethylacetate phase isdried over magnesium sulphate and evaporated to afford(2-Ethyl-2H-tetrazol-5-yl)-carbamic acid phenyl ester as a white solid.1H NMR (CDCl3, 400 MHz) δ, 7.90 (1H, brs), 7.30 (2H, m), 7.15, (3H, m),4.60 (2H, q) 1.60 (3H, t).

(3-Ethynyl-phenyl)-carbamic acid phenyl ester,(3-dimethylcarbamoyl-phenyl)-carbamic acid phenyl ester,(3-methylcarbamoyl-phenyl)-carbamic acid phenyl ester,benzothiazol-2-yl-carbamic acid phenyl ester,(4-methanesulfonyl-phenyl)-carbamic acid phenyl ester,(5-propyl-[1,3,4]thiadiazol-2-yl)carbamic acid phenyl ester,(2-ethyl-2H-tetrazol-5-yl)-carbamic acid phenyl ester,(3-sulfamoyl-phenyl)-carbamic acid phenyl ester,(1-methanesulfonyl-2,3-dihydro-1H-indol-5-yl)-carbamic acid phenylester, quinolin-6-yl-carbamic acid phenyl ester,(5-cyclo-propyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester,(2,4-dimethoxy-phenyl)carbamic acid phenyl ester,(4-methoxymethyl-phenyl)-carbamic acid phenyl ester,(4-carbamoylphenyl)-carbamic acid phenyl ester,[4-(acetyl-methyl-amino)-phenyl]carbamic acid phenyl ester,(3-isopropyl-[1,2,4]thiadiazol-5-yl)-carbamic acid phenyl ester,(3-tert-butyl-isoxazol-5-yl)carbamic acid phenyl ester,(5-methyl-isoxazol-3-yl)-carbamic acid phenyl ester,(3-methyl-[1,2,4]thiadiazol-5-yl)-carbamic acid phenyl ester,(2-cyano-4,5-dimethoxy-phenyl)-carbamic acid phenyl ester,(4-fluoro-2-methoxy-phenyl)-carbamic acid phenyl ester and(2-Fluoro-4-methoxy-phenyl)-carbamic acid phenyl ester are all madeanalogously using appropriate starting materials.

(5-Ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester

A solution of 5-Ethyl-[1,3,4]thiadiazol-2-ylamine (2.5 g, 19.4 mmol) andpyridine (1.72 ml, 21.3 mmol) in dichloromethane (70 ml) is cooled to−70° C. and treated with a solution of phenylchloroformate (2.45 ml,19.6 mmol) in dichloromethane (10 ml) dropwise. The reaction mixture isallowed to warm to ambient temperature and stirred for 3 hours duringwhich a precipitate forms. The precipitate is collected by filtration,and dried under vacuum to afford(5-Ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester as whitesolid. [M+H] 250.15

{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-carbamic acid phenylester

A solution of 3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine (0.05g, 0.223 mmol), phenylchloroformate (0.056 ml, 0.446 mmol) anddimethylaminopyridine (0.027 g, 0.223 mmol) in dichloromethane (4 ml) isstirred at ambient temperature for 24 hours. The reaction mixture isevaporated and the crude product purified by flash silica chromatography(elution 5:95 methanol/dichloromethane) to afford3-[3-(4-Fluoro-phenoxy)-azetidin-1-yl]-propyl)-carbamic acid phenylester. [MH]+ 344.9.

{3-[3-(4-Fluoro-phenoxy)-azetidin-1-yl]-propyl}-carbamic acid tert-butylester

A solution of 3-(4-fluoro-phenoxy)-azetidine hydrochloride (2.0 g, 9.85mmol) and diisopropylethylamine (4.28 ml, 24 mmol) and(3-bromo-propyl)-carbamic acid tert-butyl ester (2.84 g, 12 mmol) inacetonitrile (20 ml) is stirred at ambient temperature for 3 days. Thereaction mixture is partitioned between dichloromethane and water, theorganic phase dried over MgSO₄ and evaporated. The crude product ispurified by flash silica chromatography (elution with a 5:95methanol/dichloromethane) to afford3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl)-carbamic acid tert-butylester [MH]+ 325.1.

3-[3-(4-Fluoro-phenoxy)-azetidin-1-yl]-propylamine

A solution of 3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-carbamicacid tert-butyl ester (2.4 g, 7.4 mmol) in dichloromethane (10 ml) istreated with 4M HCl in dioxane (5.7 ml), with stirring at ambienttemperature. The solvent is evaporated and the residue partitionedbetween dichloromethane and 4M NaOH solution. The dichloromethane phaseis dried over MgSO₄ and evaporated to afford3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine. [MH]+ 225.0.

((S)-3-Hydroxy-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester

A solution of (S)-3-tert-Butoxycarbonylamino-4-methoxy-butyric acidbenzyl ester (10.4 g, 32.3 mmol) in dry diethylether (70 ml) cooled to0° C. is treated slowly with a 2.0 M solution of LiBH₄ in THF (32.2 ml,64.4 mmol). The reaction mixture is allowed to warm to ambienttemperature and then left to stir. After 6 hours the reaction mixture isquenched slowly with 0.5 M aqueous solution of citric acid and extractedwith ether. The ether phase is dried over magnesium sulphate andevaporated. The crude product is purified by flash silica chromatography(elution with a gradient 3:7 to 6:4 ethylacetate/hexane) to afford((S)-3-Hydroxy-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester asa clear oil. [M-BOC] 120.13

((R)-3-Hydroxy-1-methyl-propyl)-carbamic acid tert-butyl ester

A solution of (S)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzylester (0.2 g, 0.477 mmol) in dry diethylether (3 ml) cooled to 0° C.under argon, is treated with a 2.0 M solution of lithium borohydride inTHF (0.95 ml, 1.9 mmol). The reaction mixture is allowed to warm toambient temperature with stirring for 18 hours. The reaction is quenchedby addition of water and partitioned between ethylacetate and 10% citricacid solution. The organic phase is washed with brine, dried overmagnesium sulphate and evaporated. The crude product is purified byflash silica chromatography using 1% methanol in DCM as eluent to afford((R)-3-hydroxy-1-methyl-propyl)-carbamic acid tert-butyl ester.

((S)-3-Iodo-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester

A suspension of polystyrene resin-bound triphenylphosphine (18.645 g, 3mmol/g) in dry dichloromethane (250 ml) is treated with iodine (12.5 g,49.22 mmol) and stirred for 15 minutes under argon. Imidazole (3.87 g,55.94 mmol) is added and the reaction mixture stirred at roomtemperature for a further 15 minutes. The reaction mixture is thentreated with a solution of((S)-3-Hydroxy-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester(4.9 g, 22.37 mmol) in dichloromethane (30 ml), and refluxed for 1.5hours under argon. The resin is removed by filtration through a celitepad, washing with dichloromethane. The filtrate is washed with 5%aqueous sodium thiosulphate solution and water, dried over MgSO₄ andevaporated to afford ((S)-3-Iodo-1-methoxymethyl-propyl)-carbamic acidtert-butyl ester as a crude oil. [M-BOC] 230.06.

((R)-3-Iodo-1-methyl-propyl)-carbamic acid tert-butyl ester

A suspension of polymer bound triphenyl phosphine (0.200 g, 0.595 mmol)in DCM (2 ml) is treated with iodine (0.133 g, 0.523 mmol) and thereaction mixture stirred at ambient temperature for 15 minutes.Imidazole (39 mg, 0.57 mmol) is added and the reaction mixture stirredfor a further 15 minutes. A solution of((R)-3-Hydroxy-1-methyl-propyl)-carbamic acid tert-butyl ester (0.045 g,0.238 mmol) in DCM (2 ml) is added. The suspension is stirred at refluxfor 2.5 hours, then filtered through Celite™ filter material, washingthrough with DCM.

The combined organic phase is washed with an aqueous solution of 10%sodium thiosulphate, water and brine, then dried over magnesium sulphateand evaporated to afford ((R)-3-iodo-1-methyl-propyl)-carbamic acidtert-butyl ester. [M+H] 285.05

Pyridin-4-yl-carbamic acid phenyl ester

A solution of 4 aminopyridine (0.6 g, 6.37 mmol) in dichloromethane (15ml) is treated with triethylamine (0.89 ml, 6.37 mmol) followed byphenylchloroformate (0.80 ml, 6.37 mmol) and then stirred at roomtemperature for 3 days. The reaction mixture is partitioned betweendichloromethane and aqueous sodium bicarbonate. The organic phase isdried over magnesium sulphate and evaporated to affordpyridin-4-yl-carbamic acid phenyl ester.

(5-Methyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester,(2-methyl-thiazol-5-yl)-carbamic acid phenyl ester,(3-methyl-isoxazol-5-yl)-carbamic acid phenyl ester,pyridin-3-yl-carbamic acid phenyl ester and(3-isopropyl-isoxazol-5-yl)-carbamic acid phenyl ester are all madeanalogously using appropriate starting materials.

Quinoline-3-carboxylic acid (3-bromo-propyl)-amide

A suspension of quinoline-3-carboxylic acid (0.1 g, 0.57 mmol) indichloromethane (1.5 ml) is treated with dimethylformamide (0.02 ml) andthen oxalylchloride (0.1 ml, 1.15 mmol). The reaction mixture is stirredunder argon at ambient temperature for 1.6 hours, then evaporated toafford quinoline-3-carbonyl chloride as a crude pale yellow solid. Thecrude material is suspended in dichloromethane (2.0 ml) and treated withbromopropylamine hydrobromide (0.125 g, 0.57 mmol) and triethylamine(0.42 ml, 3 mmol). The reaction mixture is stirred at ambienttemperature for 3.25 hours, then quenched with water and partitionedbetween aqueous NaHCO₃ solution and dichloromethane. The organic phaseis washed with NaHCO₃ solution and brine, dried over MgSO₄ andevaporated. The crude product is purified by flash silica chromatography(elution ethyl acetate) to afford quinoline-3-carboxylic acid(3-bromopropyl)-amide. [MH]+ 292.9.

Preparation of Final Compounds

N-{(S)-1-tert-Butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-3,4,5-trimethoxy-benzamide—Example1

A solution of 3,4,5-trimethoxy-benzoic acid (0.246 g, 1.16 mmol) anddiisopropylethylamine (0.62 ml, 3.47 mmol) in dry dimethylformamide (10ml) is treated with [(benzotriazol-1-yloxy)-dimethylaminomethylene]-dimethyl-ammonium; tetrafluoro borate (0.32 g, 1.0 mmol). Thereaction mixture is stirred at ambient temperature for 5 minutes, then(S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine(0.968 mmol) is added and the reaction mixture stirred for 20 hours. Thedimethylformamide is evaporated and the residue partitioned betweenethylacetate and saturated aqueous NaHCO₃. The ethylacetate phase iswashed with brine, dried over MgSO₄ and evaporated. The crude product ispurified by flash silica chromatography (elution 50% ethylacetate/hexaneto 100% ethylacetate) to affordN-{(S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-3,4,5-trimethoxy-benzamide[MH]+ 505.3.

N-{(S)-3-[3-(4-Fluoro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3,4,5-trimethoxy-benzamide—Example2

A solution ofN-{(S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-3,4,5-trimethoxy-benzamide(Example 1, 0.066 g, 0.130 mmol) in dichloromethane (2 ml) is treatedwith trifluoroacetic acid (0.11 ml, 0.65 mmol) and the reaction mixturestirred for 20 hours. The solvent is evaporated and the residuepartitioned between ethylacetate and saturated aqueous NaHCO₃. Theethylacetate phase is washed with brine, dried over magnesium sulphateand evaporated. The crude product is purified by flash silicachromatography (elution 100% ethylacetate then 5:95methanol/dichloromethane) to affordN-{(S)-3-[3-(4-fluorophenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3,4,5-trimethoxy-benzamide[MH]+ 449.1.

Example 3 is prepared in analogously.

The compounds of Examples 14, 15, 17 and 18 are prepared analogouslyexcept the hydroxy chain is not protected and for Examples 17 and 18 theresulting ester is cleaved with treatment with alkali, e.g. sodiumhydroxide solution.

Quinoline-3-carboxylic acid{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-amide—Example 5

This is prepared analogously to Example 10 below, usingquinoline-3-carboxylic acid (3-bromo-propyl)-amide in place of2-(3-acetyl-phenoxy)-N-(3-bromopropyl)-acetamide.

2-(3-Acetyl-phenoxy)-N-[3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl]-acetamide—Example10

A solution of (3-acetyl-phenoxy)-acetic acid (0.194 g, 1.0 mmol) anddiisopropylethylamine (0.38 g, 3 mmol) in dry DMF (3 ml) is treated with[dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluoro phosphate (0.38 g, 1.0 mmol). After stirring for 5 minutes3-bromo-propylamine hydrobromide (0.26 g, 1.2 mmol) is added andstirring continued for a further 40 minutes. The solvent is evaporatedand the crude mixture partitioned between ethylacetate and saturatedaqueous NaHCO₃. The ethyl acetate phase is dried over MgSO₄ andevaporated to afford 2-(3-acetyl-phenoxy)-N-(3-bromopropyl)-acetamide.This crude material is taken up in acetonitrile (3 ml) and treated withtriethylamine (0.38 g, 3 mmol) and 3-(4-fluoro-phenoxy)-azetidinehydrochloride (0.11 g, 1.2 mmol). The reaction mixture is stirred atambient temperature for 20 hours, the solvent evaporated and the crudeproduct purified by flash silica chromatography (elution 10:90methanol/dichloromethane) to afford2-(3-acetyl-phenoxy)-N-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-acetamide.[MH]+ 401.14.

Examples 4, 6 to 13, 16 and 19 are prepared analogously.

1-3,4-Difluoro-phenyl)-3-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-urea—Example23

A solution of 3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine (0.04g, 0.178 mmol) and 3,4-difluorophenylisocyanate (0.020 ml, 0.178 mmol)in dichloromethane (1 ml) is stirred at room temperature for 5 hours.The solvent is evaporated and the crude product purified by flash silicachromatography (elution gradient a 3:97 to 5:95methanol/dichloromethane) to afford1-(3,4-difluoro-phenyl)-3-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-urea.[MH]+ 379.9.

Example 22 is prepared analogously.

1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(3,5-dimethoxy-phenyl)-urea—Example26

A solution of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol (0.2 g,0.74 mmol) in dichloromethane (6 ml) is treated with3,5-dimethoxy-phenyl-isocyanate (0.12 g, 0.667 mmol). The reactionmixture is stirred at ambient temperature for 24 hours and thenevaporated. The crude product is purified by flash silica chromatography(elution gradient 3:97 to 7:93 methanol/dichloromethane) to afford1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(3,5-dimethoxy-phenyl)-urea.[MH]+ 449.9.

Examples 21, 24, 25, 27 to 33, 36, 38 to 42, 44 to 48, 50 to 53, 57, 96,101, 105, 112, 196 and 203 are prepared analogously. Example 43 is madeanalogously except the benzyl group is deprotected.

1-(3,5-Dimethoxy-phenyl)-3-{(S)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-1-hydroxymethyl-propyl}-urea—Example34

A solution of1-{(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-propyl}-3-(3,5-dimethoxy-phenyl)-urea(0.862 g, 0.126 mmol) in THF (3 ml) is treated with a 1 M solution oftetrabutyl ammonium fluoride (TBAF, 0.126 ml), and the reaction mixturestirred at ambient temperature for 2 hours. The reaction mixture ispartitioned between ethylacetate and saturated NaHCO₃ solution. Theethylacetate phase is washed with water and brine, dried over MgSO₄ andevaporated. The crude product is purified by flash silica chromatography(elution with a 5:95 methanol/dichloromethane) to afford1-(3,5-dimethoxy-phenyl)-3-{(S)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-1-hydroxymethyl-propyl}-urea.

Examples 35, 37, 49, 90, 114 and 120 are prepared analogously.

1-Cyclohexyl-3-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-1-methyl-urea—Example54

A solution of 3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl)-carbamicacid phenyl ester (0.035 g, 0.101 mmol) and N-methylcyclohexylamine(0.02 ml, 0.15 mmol) in dimethylsulphoxide (1 ml) is stirred at ambienttemperature for 2 days. The reaction mixture is partitioned betweenethylacetate and water, the organic phase dried over MgSO₄ andevaporated. The crude product is purified by flash silica chromatography(elution 5:95 methanol/dichloromethane) to afford1-cyclohexyl-3-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl)-1-methyl-urea.

3,4-Dihydro-2H-quinoline-1-carboxylic acid{3-[3-(4-fluorophenoxy)-azetidin-1-yl]-propyl}-amide—Example 55

A solution of 1-Bromo-3-isocyanato-propane (0.164 g, 1.0 mmol) inacetonitrile is stirred with 1,2,3,4-Tetrahydro-quinoline (0.133 g, 1.0mmol) and diisopropylethylamine (0.2 ml, 1.2 mmol). The reaction mixtureis stirred for 2 hours at ambient temperature and then the solventremoved. The crude product is taken-up in acetonitrile (4 ml) anddiisopropylethylamine (0.2 ml, 1.2 mmol) and3-(4-Fluoro-phenoxy)-azetidine hydrochloride (0.11 g, 1.0 mmol) added.The reaction mixture is stirred at ambient temperature for 18 hours, thesolvent evaporated and the crude partitioned between ethylacetate andsaturated sodium bicarbonate solution. The organic phase is washed withbrine, dried over magnesium sulphate and evaporated. The crude productis purified by flash silica chromatography (elution gradientethylacetate then 5:95 methanol/dichloromethane) to afford3,4-Dihydro-2H-quinoline-1-carboxylic acid{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-amide. [MH]+ 444.2

1-{3-[3-(4-Fluoro-phenoxy)-azetidin-1-yl]-propyl}-3-(3-methoxy-phenyl)-urea—Example56

A solution of 3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine (0.07g, 0.31 mmol) and 1-isocyanato-3-methoxy-benzene (0.041 g, 0.31 mmol) indioxane (15 ml) is heated to 100° C. for 3 hours. The reaction mixtureis evaporated and the crude product purified by flash silicachromatography (elution with a 1:9 methanol/dichloromethane) to afford1-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-3-(3methoxy-phenyl)-urea.[MH]+ 374.0.

Examples 20 is are prepared analogously.

3-Cyano-N-{3-[3-(4-fluoro-phenoxy)-azetidin-4-yl]-propyl}-benzenesulfonamide—Example58

A suspension of 3-(4-fluoro-phenoxy)-azetidine hydrochloride (0.049 g,0.24 mmol) in acetonitrile (1.0 ml) is treated with the crudeN-(3-bromo-propyl)-3-cyano-benzenesulfonamide (0.072 g) in acetonitrile(1.0 ml) and triethylamine (0.1 ml, 0.72 mmol). The resulting homogenousreaction mixture is stirred at ambient temperature for 70 hours, thesolvent evaporated and the residue partitioned between ethylacetate andaqueous NaHCO₃ solution. The ethylacetate phase is washed with brine,dried over MgSO₄ and evaporated. The crude product is purified by flashsilica chromatography (elution ethylacetate) to afford3-cyano-N-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-benzenesulfonamide.[MH]+ 390.

Examples 59 to 65 are prepared analogously.

1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxyethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea—Example78

A solution of(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propylamine(1.6 g, 5.6 mmol) and (5-Ethyl-2-methyl-2H-pyrazol-3-yl)-carbamic acidphenyl ester (1.65 g, 6.7 mmol, see preparation below) in DMSO (7 ml) isstirred at ambient temperature for 4 hours, then partitioned betweenwater and ethylacetate. The organic phase is washed again with water,dried over MgSO4 and evaporated. The crude product is purified by flashsilica chromatography (elution with a 5:95 methanol/dichloromethane) toafford1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea.[M+H] 436.37.

Examples 69, 70, 75, 76, 80, 89, 93 and 116 are prepared analogously

1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-urea—Example83

A solution of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol (0.158 g,0.58 mmol) and (5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-carbamic acidphenyl ester (0.150 g, 0.58 mmol) in DMSO (3 ml) is stirred at ambienttemperature for 6 hours, then partitioned between water andethylacetate. The organic phase is washed again with water, dried overMgSO₄ and evaporated. The crude product is purified by flash silicachromatography (elution with a 10:90 methanol/dichloromethane) to afford1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-urea.[M+H] 434.33.

The compounds of Examples 66, 67, 71 to 74, 77, 79, 81 to 88, 91, 92,94, 95, 97, 98, 100, 102, 103, 104, 106 to 111, 113, 115, 117 to 119,121 and 123 to 128 are prepared analogously using an appropriatecarbamic acid phenyl ester.

1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea—Example88

A solution of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol (0.45 g, 2mmol) and (5-Ethyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester(0.49 g, 1.66 mmol) in DMSO (5 ml) is stirred at ambient temperature for1 hour, then partitioned between water and ethylacetate. The organicphase is dried over MgSO₄ and evaporated. The crude product is purifiedby recrystallisation from hot ethylacetate to afford1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea.

1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea—Example99

A solution of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride (1.04 g, 2.82 mmol),(5-Ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester (0.70 g,2.82 mmol) and triethylamine (1.6 ml, 11.28 mmol) in DMSO (70 ml) isstirred at ambient temperature for 18 hour, then partitioned betweenethylacetate and saturated aqueous sodium bicarbonate solution. Theorganic phase is washed with brine, dried over MgSO₄ and evaporated. Thecrude product is purified by recrystallisation from hot ethylacetate toafford1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea.[M+H] 426.18.

The compound of Example 129 is prepared analogously using(S)-2-amino-4-[3-(4-chlorophenoxy)-azetidin-1-yl]-propan-1-ol instead of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol. Where(S)-2-Amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-propan-1-ol isprepared analogously to(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol exceptusing NBOC-D serine instead of (S)-2-tert-butoxycarbonylamino-succinicacid.

Acetic acid(S)-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-2-[3-(3,5-dimethoxy-phenyl)-ureido]-butylester—Example 122

A solution of1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(3,5-dimethoxy-phenyl)-urea(0.05 g, 0.111 mmol) and triethylamine (0.031 ml, 0.222 mmol) in DCM (3ml) is treated with acetic anhydride and left to stir at roomtemperature for 3 hours. The reaction mixture is partitioned between DCMand water. The organic phase is washed with sodium bicarbonate solution,dried over magnesium sulphate and evaporated to afford acetic acid(S)-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-2-[3-(3,5-dimethoxy-phenyl)-ureido]-butylester. [M+H] 492.08

3-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxmethyl-propyl}-1-(3,5-dimethoxy-phenyl)-1-methyl-urea—Example1301-{(S)-1-(tert-Butyl-diphenyl-silanyloxymethyl)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-propyl}-3-(3,5-dimethoxy-phenyl)-1-methyl-urea

A solution of(S)-1-(tert-Butyl-diphenyl-silanyloxymethyl)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-propylamine(0.1 g, 0.196 mmol), (3,5-Dimethoxy-phenyl)-methyl-carbamoyl Chloride(45 mg, 0.19 mmol) and triethylamine (0.027 ml, 0.19 mmol) indichloromethane (2 ml) is stirred at room temperature for 2 days. Thereaction mixture is washed with water, dried over magnesium sulphate andevaporated. The crude product is chromatographed over flash silica usingethyl acetate as eluent to afford1-{(S)-1-(tert-Butyl-diphenyl-silanyloxymethyl)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-propyl}-3-(3,5-dimethoxy-phenyl)-]-methyl-urea.[M+H] 702.3

3-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxyethyl-propyl}-1-(3,5-dimethoxy-phenyl)-1-methyl-urea

1-{(S)-1-(tert-Butyl-diphenyl-silanyloxymethyl)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-propyl}-3-(3,5-dimethoxy-phenyl)-1-methyl-ureais deprotected in the same manner as1-(3,5-Dimethoxy-phenyl)-3-{(S)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-1-hydroxymethyl-propyl}-ureain Example 34 to afford3-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-1-(3,5-dimethoxy-phenyl)-1-methyl-urea.[M+H] 463.5

1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(3-methoxy-phenyl)-thiourea—Example131

This compound is prepared in a manner analogous to that used to prepare1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(3,5-dimethoxy-phenyl)-ureain Example 26 except in the final step the isocyanate is replaced withthe appropriate isothiocyanate.

The compounds of Examples 132 and 133 are prepared analogously.

1-{(S)-3-[3-(3,4-dichloro-phenoxy)-azetidin-1-yl]-1-hydroxyethyl-propyl}-3-(5-cycle-propyl-2-methyl-2H-pyrazol-3-yl)-urea—Example134

This compound is prepared analogously to1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-ureain Example 83 except using(S)-2-amino-4-[3-(3,4-dichloro-phenoxy)-azetidin-1-yl]-butan-1-ol inplace of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol.

The compounds of Examples 135 to 137 are prepared analogously using theappropriate halo-substituted phenoxy-azetidine compound.

1-{(S)-3-[3-(3,4-dichloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea—Example138

This compound is prepared in a manner analogous to that used to prepare1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-ureain Example 88 except using(S)-2-amino-4-[3-(3,4-dichloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

The compounds of Examples 139 to 141 are prepared analogously using theappropriate halo-substituted phenoxy-azetidine compound.

1-{(S)-3-[3-(4-chloro-3-fluoro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea—Example142

This compound is prepared analogously to1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4-thiadiazol-2-yl)-ureain Example 99 except using(S)-2-amino-4-[3-(4-chloro-3-fluoro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

The compounds of Examples 143 and 144 are prepared analogously using theappropriate halo-substituted phenoxy-azetidine compound.

1-{(S)-3-[3-(4-fluoro-benzyl)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclo-propyl-2-methyl-2H-pyrazol-3-yl)-urea—Example145

This compound is prepared in a manner analogous to that used to prepare1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-ureain Example 83 except using(S)-2-amino-4-[3-(4-fluoro-benzyl)-azetidin-1-yl]-butan-1-ol in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol.

The compounds of Examples 146 to 149 are prepared analogously using theappropriate halo-substituted benzyl-azetidine compound.

1-{(S)-3-[3-(4-fluoro-benzyl)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea—Example150

This compound is prepared analogously to1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-ureain Example 88 except using(S)-2-amino-4-[3-(4-fluoro-benzyl)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

The compounds of Examples 151 to 154 are prepared analogously using theappropriate halo-substituted benzyl-azetidine compound.

1-{(S)-3-[3-(4-fluoro-benzyl)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea—Example155

This compound is prepared analogously to1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-ureain Example 99 except using(S)-2-amino-4-[3-(4-fluoro-benzyl)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

The compounds of Examples 156 to 159 are prepared analogously using theappropriate halo-substituted benzyl-azetidine compound.

1-{(S)-3-[3-(4-chloro-3-fluoro-benzol)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclo-propyl-2-methyl-2H-pyrazol-3-yl)-urea—Example160

This compound is prepared analogously to1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-ureain Example 83 except using(S)-2-amino-4-[3-(4-chloro-3-fluoro-benzyl)-azetidin-1-yl]-butan-1-ol inplace of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol.

The compounds of Examples 161 and 162 are prepared analogously using theappropriate halo-substituted benzoyl-azetidine compound.

1-{(S)-3-[3-(4-chloro-3-fluoro-benzoyl)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea—Example163

This compound is prepared analogously to1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-ureain Example 88 except using(S)-2-amino-4-[3-(4-chloro-3-fluoro-benzoyl)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

The compounds of Examples 164 and 165 are prepared analogously using theappropriate halo-substituted benzoyl-azetidine compound.

1-{(S)-3-[3-(4-chloro-3-fluoro-benzoyl)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea—Example166

This compound is prepared analogously to1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-ureain Example 99 except using(S)-2-amino-4-[3-(4-chloro-3-fluoro-benzoyl)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

The compounds of Examples 167 and 168 are prepared analogously using theappropriate halo-substituted benzoyl-azetidine compound.

1-{(S)-3-[3-phenoxy-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea—Example169

This compound is prepared analogously to1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-ureain Example 99 except using(S)-2-amino-4-[3-phenoxy-azetidin-1-yl]-butan-1-ol hydrochloride inplace of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

1-{(S)-3-[3-(3-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea—Example170

This compound is prepared analogously to1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-ureain Example 99 except using(S)-2-amino-4-[3-(3-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

The compound of Example 171 is prepared analogously using(S)-2-amino-4-[3-(3-fluoro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

1-{(S)-3-[3-(4chloro-3-methyl-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclo-propyl-2-methyl-2H-pyrazol-3-yl)-urea—Example172

This compound is prepared analogously to1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-ureain Example 83 except using(S)-2-amino-4-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-butan-1-olin place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol.

The compounds of Examples 173 to 177 are prepared analogously using theappropriate methyl and halo-substituted phenoxy/benzyl/benzoyl-azetidinecompound.

1-{(S)-3-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea—Example178

This compound is prepared analogously to1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-ureain Example 88 except using(S)-2-amino-4-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

The compounds of Examples 179 and 183 are prepared analogously using theappropriate methyl and halo-substituted phenoxy/benzyl/benzoyl-azetidinecompound.

1-{(S)-3-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl]-urea—Example184

This compound is prepared analogously to1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-ureain Example 99 except using(S)-2-amino-4-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

The compounds of Examples 185 to 189 are prepared analogously using theappropriate methyl and halo-substituted phenoxy/benzyl/benzoyl-azetidinecompound.

1-{(S)-3-[3-(4-chloro-benzyl)-azetidin-yl]-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-yl)-urea—Example190

A solution of 3-[3-(4 chloro-benzyl)-azetidin-1-yl]-propylamine (0.100mg, 0.418 mmol) and (5-ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acidphenyl ester (0.11 mg, 0.439 mmol) in DMSO is stirred at roomtemperature for 18 hours then partitioned between ethylacetate andwater. The organic phase is washed with brine and dried over magnesiumsulphate and evaporated. The crude product is purified by flash silicachromatography using 5% methanol in DCM as eluent to afford1-{3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea.[M+H] 394.1

1-{(R)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea—Example191

A solution of(R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propylamine (0.145mg, 0.569 mmol) and (5-ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acidphenyl ester (0.142 mg, 0.569 mmol) in DMSO is stirred at roomtemperature for 4 hours then partitioned between ethylacetate and water.The organic phase is washed with brine and dried over magnesium sulphateand evaporated. The crude product is recrystallised from hotethylacetate to afford1-{(R)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea.[M+H] 410.14.

1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-isoxazol-3-yl)-urea—Example192

This compound is prepared analogously to Example 88 but using(5-ethyl-isoxazol-3-yl)-carbamic acid phenyl ester in place of(5-ethyl-2-methyl-2H-pyrazol-3-yl))-carbamic acid phenyl ester.

The compounds of Examples 193 to 195 are prepared analogously using theappropriate carbamic acid phenyl ester. In each case the relevantheterocycle is made in a manner analogous to that used to prepare5-ethyl-2-methyl-2H-pyrazol-3-ylamine except methyl hydrazine isreplaced with the appropriate alkyl-hydrazine.

1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxmethyl-propyl}-3-cycloheptyl-urea—Example196

This compound is prepared analogously to Example 26.

1-{(S)-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea—Example197

This compound is prepared analogously to1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-ureain Example 99 except using(S)-2-amino-4-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

1-{(S)-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclo-propyl-2-methyl-2H-pyrazol-3-yl)-urea—Example198

This compound is prepared analogously to1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-ureain Example 83 except using(S)-2-amino-4-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-butan-1-ol in placeof (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol.

1-{(S)-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea—Example199

This compound is prepared analogously to1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-ureain Example 88 except using(S)-2-amino-4-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride in place of(S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-olhydrochloride.

1-{(S)-3-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl-propyl}-3-(5-ethyl-(1,3,4]thiadiazol-2-yl)-urea—Example200

The compound of this Example is made in a manner analogous to that usedto prepare1-{(S)-3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-ureain Example 192 but using3-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-propylamine in place of3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propylamine. [M+H] 410.2

1-{(S)-3-[3-(3,4-dichloro-phenoxy)-azetidin-1-yl]-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea—Example201

This compound is prepared analogously to{(S)-3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-ureain Example 192 but using3-[3-(3,4-dichloro-phenoxy)-azetidin-1-yl]-propylamine in place of3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propylamine. [M+H] 430.1

1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-methyl-isoxazol-3-yl-methyl)-urea—Example202

This compound is prepared analogously to Example 88 but using(5-methyl-isoxazol-3-yl-methyl)-carbamic acid phenyl ester in place of(5-ethyl-2-methyl-2H-pyrazol-3-yl))-carbamic acid phenyl ester.

1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-cyclopentyl-urea—Example203

This compound is prepared analogously to Example 26.

1. A compound of formula I

in free or salt form, where Ar is phenyl optionally substituted by oneor more substituents selected from halogen, C₁-C₈-alkyl, cyano or nitro;R¹ is hydrogen or C₁-C₈-alkyl optionally substituted by hydroxy,C₁-C₈-alkoxy, acyloxy, halogen, carboxy, C₁-C₈-alkoxycarbonyl, —N(R⁴)R⁵,—CON(R⁶)R⁷ or by a monovalent cyclic organic group having 3 to 15 atomsin the ring system; R² is hydrogen, C₁-C₈-alkyl or C₃-C₁₀-cycloalkyl; R³is a heterocyclic group having 5 to 11 ring atoms of which 1 to 4 arehetero atoms selected from nitrogen, oxygen and sulphur atoms; R⁴ and R⁵are each independently hydrogen or C₁-C₈-alkyl, or R⁴ is hydrogen and R⁵is hydroxy-C₁-C₈-alkyl, acyl, —SO₂R⁸ or —CON(R⁶)R⁷, or R⁴ and R⁵together with the nitrogen atom to which they are attached denote a 5-or6-membered heterocyclic group; R⁶ and R⁷ are each independently hydrogenor C₁-C₈-alkyl, or R⁶ and R⁷ together with the nitrogen atom to whichthey are attached denote a 5- or 6-membered heterocyclic group; R⁸ isC₁-C₈-alkyl, C₁-C₈-haloalkyl, or phenyl optionally substituted byC₁-C₈-alkyl; X is —C(═O)—, —O—, —CH₂—, or CH(OH); Y is oxygen or sulfur;m is 1, 2, 3 or 4; and n, p and q are each 0 or 1, n+p+q=1 or 2, n+q=1,p+q=1, and when n is 0, p is
 0. 2. A compound according to claim 1, inwhich Ar is phenyl substituted by one or two substituents selected fromhalogen and C₁-C₈-alkyl; R¹ is hydrogen, C₁-C₄-alkyl optionallysubstituted by hydroxy or C₁-C₈-alkoxy, acyloxy, C₁-C₈-alkyl substitutedby benzoyloxy or phenoxy-C₁-C₄-alkylcarbonyloxy which are optionallysubstituted in the benzene ring by at least one substituent selectedfrom C₁-C₈-alkoxy, C₁-C₈-alkylcarbonyl and aminosulfonyl, or C₁-C₈-alkylsubstituted by naphthyl; R² is hydrogen or C₁-C₈-alkyl, R³ is aheterocyclic group having 5 to 11 ring atoms of which 1 to 4 are heteroatoms selected from nitrogen, oxygen and sulphur atoms; X is —O—,—C(═O)— or —CH₂—; Y is oxygen or sulfur; and m is 1, 2, 3 or
 4. 3. Acompound according to claim 1, in which Ar is phenyl substituted by oneor two substituents selected from halogen and C₁-C₄-alkyl; R¹ ishydrogen, C₁-C₄-alkyl optionally substituted by hydroxy or C₁-C₄-alkoxy,acyloxy, C₁-C₄-alkyl substituted by benzoyloxy orphenoxy-C₁-C₄-alkylcarbonyloxy which are optionally substituted in thebenzene ring by at least one substituent selected from C₁-C₄-alkoxy,C₁-C₄-alkylcarbonyl and aminosulfonyl, or C₁-C₄-alkyl substituted bynaphthyl; R² is hydrogen or C₁-C₄-alkyl, R³ is a heterocyclic grouphaving 5 to 11 ring atoms of which 1 to 4 are hetero atoms selected fromnitrogen, oxygen and sulphur atoms; X is —O—, —C(═O)— or —CH₂—; Y isoxygen or sulfur; and m is 1, 2, 3 or
 4. 4. A compound according toclaim 1, which is of formula II

where Ar is phenyl substituted by one or two substituents selected fromfluorine and chlorine, one of said substituents being para to theindicated group X, R¹ is hydrogen, C₁-C₄-alkyl substituted by hydroxy orC₁-C₄-alkoxy, C₁-C₄-alkyl substituted by benzoyloxy orphenoxy-C₁-C₄-alkylcarbonyloxy which are optionally substituted in thebenzene ring by at least one substituent selected from C₁-C₄-alkoxy,C₁-C₄-alkylcarbonyl and aminosulfonyl, or C₁-C₄-alkyl substituted bynaphthyl, R³ is a heterocyclic group having 5 to 11 ring atoms of which1 to 4 are hetero atoms selected from nitrogen, oxygen and sulphuratoms; X is —O—, and m is 2 or
 3. 5. A compound according to claim 1,which is of formula III

where Ar is phenyl substituted by one or two substituents selected fromfluorine and chlorine, one of said substituents being para to theindicated group X, R¹ is hydrogen, C₁-C₄-alkyl substituted by hydroxy orC₁-C₄-alkoxy, R² is hydrogen or C₁-C₄-alkyl R³ is a heterocyclic grouphaving 5 to 11 ring atoms of which 1 to 4 are hetero atoms selected fromnitrogen, oxygen and sulphur atoms; X is —O— or —C(═O)—, and m is 2 or3.
 6. A compound according to claim 1, which is also of formula III,

where Ar is phenyl substituted by chlorine para to the indicated group Xand optionally also substituted by chlorine meta to the indicated groupX, R¹ is hydrogen or C₁-C₄-alkyl substituted by hydroxy, C₁-C₄-alkoxy orC₁-C₄-acyloxy, R² is hydrogen, R³ is a heterocyclic group having 5 to 11ring atoms of which 1 to 4 are hetero atoms selected from nitrogen,oxygen and sulphur atoms X is —O—, —CH₂— or —C(═O)—, and m is
 2. 7. Acompound according to claim 1, which is also of formula IIIa

where Ar is phenyl optionally substituted by fluoro or chloro para tothe indicated group X and/or optionally substituted by fluoro, chloro orC₁-C₄-alkyl meta to the indicated group X; R¹ is hydrogen or C₁-C₄-alkyloptionally substituted by hydroxy; R² is hydrogen or C₁-C₄-alkyl; R³ isa heterocyclic group having 5 to 11 ring atoms of which 1 to 4 arehetero atoms selected from nitrogen, oxygen and sulphur; X is —O—, —CH₂—or —C(═O)—; Y is O or S; and m is 1 or
 2. 8. A compound according toclaim 1, which is of formula IV

where Ar is phenyl substituted by one or two substituents selected fromfluorine and chlorine, one of said substituents being para to theindicated group X, R¹ is hydrogen or C₁-C₄-alkyl substituted by hydroxyor C₁-C₄-alkoxy, R³ is R³ is an aromatic N-or S-heterocyclic grouphaving 5 to 10 ring atoms; X is —O— and m is 2 or
 3. 9. A compoundaccording to claim 1, where Ar is phenyl optionally substituted by oneor more substituents selected from halogen, C₁-C₈-alkyl, cyano or nitro,R¹ is hydrogen or C₁-C₈-alkyl optionally substituted by hydroxy,C₁-C₈-alkoxy, acyloxy, halogen, carboxy, C₁-C₈-alkoxycarbonyl, —N(R⁴)R⁵,—CON(R⁶)R⁷ or by a monovalent cyclic organic group having 3 to 15 atomsin the ring system, R² is hydrogen or C₁-C₈-alkyl and R³ is C₁-C₈-alkylsubstituted by phenyl, phenoxy, acyloxy or naphthyl, R³ is aheterocyclic group having 5 to 11 ring atoms of which 1 to 4 are heteroatoms selected from nitrogen, oxygen and sulphur atoms; R⁴ and R⁵ areeach independently hydrogen or C₁-C₈-alkyl, or R⁴ is hydrogen and R⁵ ishydroxy-C₁-C₈-alkyl, acyl, —SO₂R⁸ or —CON(R⁶)R⁷, or R⁴ and R⁵ togetherwith the nitrogen atom to which they are attached denote a 5-or6-membered heterocyclic group, R⁶ and R⁷ are each independently hydrogenor C₁-C₈-alkyl, or R⁶ and R⁷ together with the nitrogen atom to whichthey are attached denote a 5- or 6-membered heterocyclic group, R⁸ isC₁-C₈-alkyl, C₁-C₈-haloalkyl, or phenyl optionally substituted byC₁-C₈-alkyl, X is —C(═O)—, —O—, —CH₂—, or CH(OH), Y is oxygen or sulfur,m is 1, 2, 3 or 4, and n, p and q are each 0 or 1, n+p+q=1 or 2, n+q=1,p+q=1, and when n is 0, p is
 0. 10. A compound according to claim 1,where Ar is phenyl optionally substituted by one or more substituentsselected from halogen, C₁-C₈-alkyl, cyano or nitro, R¹ is hydrogen orC₁-C₈-alkyl optionally substituted by hydroxy, C₁-C₈-alkoxy, acyloxy,halogen, carboxy, C₁-C₈-alkoxycarbonyl, —N(R⁴)R⁵, —CON(R⁶)R⁷ or by amonovalent cyclic organic group having 3 to 15 atoms in the ring system,R² is hydrogen or C₁-C₈-alkyl R³ is a heterocyclic group having 5 to 11ring atoms of which 1 to 4 are hetero atoms selected from nitrogen,oxygen and sulphur atoms; R⁴ and R⁵ are each independently hydrogen orC₁-C₈-alkyl, or R⁴ is hydrogen and R⁵ is hydroxy-C₁-C₈-alkyl, acyl,—SO₂R⁸ or —CON(R⁶)R⁷, or R⁴ and R⁵ together with the nitrogen atom towhich they are attached denote a 5-or 6-membered heterocyclic group, R⁶and R⁷ are each independently hydrogen or C₁-C₈-alkyl, or R⁶ and R⁷together with the nitrogen atom to which they are attached denote a 5-or 6-membered heterocyclic group, R⁸ is C₁-C₈-alkyl, C₁-C₈-haloalkyl, orphenyl optionally substituted by C₁-C₈-alkyl, X is —C(═O)—, —O—, —CH₂—,or CH(OH), Y is oxygen or sulfur, m is 1, 2, 3 or 4, and n, p and q areeach 0 or 1, n+p+q=1 or 2, n+q=1, p+q=1, and when n is 0, p is
 0. 11. Acompound according to claim 1 that is also a compound of formula II

where m is 2 and Ar, X, R¹ and R³ are as shown in the following table ArX R¹ R³

—O— H

—O— H

—O— H

—O— H

—O— H

—O— H

—O—

—O— H


12. A compound of claim 1 that is also a compound of formula III

where Ar, X, m, R¹, R² and R³ are as shown in the following table Ar X mR¹ R² R³

—O— 2 H —H


13. A compound of claim 1 that is also a compound of formula

where Ar, X, m, and R1 are as shown in the following table Ar X m R¹

—O— 2 H.


14. A compound of claim 1 that is also of a compound of formula IV

where m is 2, X is O, R¹ is hydrogen, and Ar and R³ are as shown in thefollowing table Ar R³


15. A compound of claim 1 that is also a compound of formula III

where m is 2, R² is hydrogen, and Ar, X, R¹ and R² are as shown in thefollowing table Ar X R¹ R³

—O—

—O—

—O— —H

—CH₂—

—CH₂—

—CH₂—

—CH₂—

—CH₂—

—CH₂—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—

—O—


16. A compound of claim 1 that is also a compound of formula IIIa

where Ar, X, m, R¹, Y, R² and R³ are as shown in the following table ArX m R¹ Y R² R³

—O— 1

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

2

O H

2

O H

2

O H

2

O H

2

O H

2

O H

2

O H

2

O H

2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

2

O H

2

O H

—O— 2

O H

—O— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

2

O H

2

O H

—O— 2

O H

—O— 2

O H

—CH₂— 2

O H

—CH₂— 2

O H

2

O H

2

O H

—CH₂— 2

O H

—CH₂— 2 —CH₃ O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2

O H

—O— 2 H O H

—O— 2 H O H

—O— 2

O H


17. A pharmaceutical composition comprising as active ingredient acompound of formula I as defined in claim
 1. 18. A pharmaceuticalcomposition comprising a compound of formula I as defined in claim 1 incombination with another drug substance which is an anti-inflammatory, abronchodilator or an antihistamine.
 19. A process for the preparation ofa compound of formula I as defined in claim 1 which comprises (i) (A)for the preparation of compounds of formula I where n is 1, p is 1, q is0 and R² is hydrogen, reacting a compound of formula V

where Ar, X, m and R¹ are as defined in claim 1, with a compound offormula VIY═C═N—R³  VI where Y and R³ are as defined in claim 1, with the provisothat when R¹ contains a reactive functional group it may be in protectedform, and, where R¹ in the product contains a protected functionalgroup, replacing the protecting group by hydrogen; (B) for thepreparation of compounds of formula I where n is 1, p is 1, q is 0 andR² is hydrogen or C₁-C₈-alkyl, reacting a compound of formula VII

where Ar, X, m and R¹ are as defined in claim 1, with a compound offormula VIII

where R² and R³ are as defined in claim 1, or and, where R¹ in theproduct contains a protected functional group, replacing the protectinggroup by hydrogen; (C) for the preparation of compounds of formula Iwhere n is 1, p is 1, q is 0 and R² and R³ together with the nitrogenatom to which they are attached denote a heterocyclic group, reacting acompound of formula IX

where Ar and X are as defined in claim 1, with a compound of formula X

where m, R¹ and Y are as defined in claim 1, R² and R³ together with thenitrogen atom to which they are attached denote a heterocyclic grouphaving 5 to 10 ring atoms of which one, two or three are hetero atoms,and L is halogen; (D) for the preparation of compounds of formula I whenn is 1, p is 0, q is 0 and Y is oxygen, reacting a compound of formulaIX where Ar and X are as defined in claim 1, with a compound of formulaXI

where L, m, R¹ and R³ are as defined in claim 1; (E) for the preparationof compounds of formula I where n is 1, p is 0, q is 0 and Y is oxygen,reacting a compound of formula V where Ar, X, m and R¹ are as defined inclaim 1, with a compound of formula XII

where R³ is as defined in claim 1, and, where R¹ in the product containsa protected functional group, replacing the protecting group byhydrogen; (F) for the preparation of compounds of formula I where n is1, p is 0, q is 0, R² is hydrogen and Y is oxygen, reacting a compoundof formula V where Ar, X, m and R¹ are as defined in claim 1, with acompound of formula XIII

where R³ is as defined in claim 1, and, where R¹ in the product containsa protected functional group, replacing the protecting group byhydrogen; (G) for the preparation of compounds of formula I where n is0, p is 0, and q is 1, reacting a compound of formula IX where Ar and Xare as defined in claim 1 in the form of a hydrohalide salt with acompound of formula XIV

where L, m, R¹ and R³ are as defined in claim 1; (H) for the preparationof compounds of formula I where n is 1, p is 1, q is 0 and Y is oxygen,reacting a compound of formula V where Ar, X, m and R¹ are as defined inclaim 1, with a compound of formula XV

where R² and R³ are defined in claim 1; or for the preparation oncompounds of formula I where n is 1, p is 0, q is 0, Y is oxygen and R²is C₁-C₈-alkyl or C₃-C₁₀-cycloalkyl, reacting a compound of formula Vwhere Ar, X, m and R¹ are as defined in claim 1, with a compound offormula XVI

where R² is C₁-C₈-alkyl or C₃-C₁₀-cycloalkyl, R³ is as defined in claim1 and Z is a halogen, with the proviso that when R¹ contains a reactivefunctional group it may be in protected form, and, where R¹ in theproduct contains a protected functional group, replacing the protectinggroup by hydrogen; and (ii) recovering the product in free or salt form.